Explorations of the Use of Olanzapine for Management of Chemotherapy-Induced Nausea and Vomiting in Children

Explorations of the use of Olanzapine for Management of Chemotherapy-induced Nausea and Vomiting in Children

Jacqueline Flank

A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmaceutical Sciences University of Toronto

Explorations of the use of Olanzapine for Management of Chemotherapy-induced Nausea and Vomiting in Children

Jacqueline Flank

Master of Science

Graduate Department of Pharmaceutical Sciences University of Toronto

2015 Abstract

Control of chemotherapy-induced nausea and vomiting (CINV) in children is sub-optimal and it continues to be a bothersome adverse effect. Effective new antiemetic interventions are required to improve CINV control. The purpose of the projects encompassed in this thesis was to explore the use of olanzapine for management of CINV in children. A systematic review of the safety of olanzapine in children was completed to determine if adverse effects would preclude evaluation of its use for CINV. A retrospective review summarized its efficacy and safety in children with cancer. Based on the results of these projects, olanzapine appears to be safe for use in children with cancer and improved CIV control rates may be achievable when olanzapine is added to antiemetics consistent with clinical practice guidelines. Overall, olanzapine appears to be a promising intervention for management of CINV in children and future prospective, controlled trials evaluating its use are warranted.

Acknowledgments

I would like to extend my sincerest gratitude to my supervisor Lee Dupuis for her continued support and mentorship while completing my thesis. I am incredibly grateful for her ongoing encouragement and the many learning opportunities provided to me while completing my Masters requirements. I would also like to acknowledge the members of my thesis committee who provided me with valuable advice and constructive feedback: Scott Walker, Lillian Sung, Beth Sproule, and Winnie Seto. The manuscripts encompassed in my thesis would not have been possible without the contributions of all of the co-authors involved: Lee Dupuis, Lillian Sung, Christopher Dvorak, Wendy Spettigue, Jennifer Thackray, Danelle Nielson, Amanda August, Tal Schechter, and Sarah Alexander. I would also like to thank the Garron Family Cancer Center for their generous financial support through a research fellowship over the past 2 years.

In addition, I would like to thank the wonderful patients and families who have participated in research projects I have worked on recently – your positivity and determination have been an incredible inspiration.

Lastly, I would like to thank my friends and family for their support – your patience, understanding, and love have truly helped me move one step closer to achieving my goals.

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Table of Contents

Acknowledgments ...... iii

Table of Contents ...... iv

List of Tables ...... vi

List of Figures ...... vii

List of Abbreviations ...... viii

Chapter 1: Introduction ...... 1

1.1 Chemotherapy-induced Nausea and Vomiting ...... 1

1.2 Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting ...... 3

1.3 Olanzapine ...... 5

1.4 Project Rationale and Purpose of Studies ...... 7

Chapter 2: The Safety of Olanzapine in Young Children: A Systematic Review and Meta- Analysis ...... 8

2.1 Abstract ...... 9

2.2 Introduction ...... 9

2.3 Methods ...... 10

2.3.1 Search Strategy and Data Sources ...... 10

2.3.2 Study Selection ...... 11

2.3.3 Data Collection Process and Quality Assessment ...... 12

2.3.4 Meta-Analysis ...... 13

2.4 Results ...... 13

2.4.1 Therapeutic Use of Olanzapine: Prospective Studies ...... 14

2.4.2 Therapeutic Use of Olanzapine: Retrospective Reviews ...... 16

2.4.3 Therapeutic Use of Olanzapine: Case Reports and Case Series ...... 16

2.4.4 Olanzapine Overdose/Poisoning: Case Reports ...... 17

2.5 Discussion ...... 17 iv

2.6 Conclusions ...... 20

Chapters 3: Olanzapine for Treatment and Prevention of Acute Chemotherapy-induced Vomiting in Children: A Retrospective, Multi-center Review ...... 68

3.1 Abstract ...... 69

3.2 Introduction ...... 69

3.3 Methods ...... 70

3.4 Results ...... 72

3.5 Discussion ...... 75

3.6 Conclusion...... 78

Chapter 4: Discussion and Conclusions ...... 83

4.1 Summary of Key Findings ...... 83

4.1.1 Safety Findings ...... 85

4.1.2 Efficacy Findings ...... 86

4.2 Strengths and Limitations ...... 88

4.3 Recommendations for Future Research ...... 89

4.5 Conclusion...... 90

References ...... 92

List of Tables

The safety of olanzapine in young children: a systematic review and meta-analysis

Table 2.1 Complete search strategy…………….……………………………………………….25

Table 2.2 Characteristics of included studies….………………………………………………...28

Table 2.3 Summary of randomized controlled trials, prospective studies, and

retrospective reviews...... ………………………………………………………………..34

Table 2.4 Synthesized adverse effects associated with olanzapine in young children…………..57

Table 2.5 Summary of adverse effects associated with olanzapine administration reported in

all included prospective studies and which were excluded from synthesis……………...58

Table 2.6 Summary of case reports..…………………………………………………………….59

Table 2.7 Summary of overdose/toxic dose articles……………………………………………..63

Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review

Table 3.1 Demographic data for 60 patients receiving olanzapine for chemotherapy-

induced nausea and vomiting control during 158 chemotherapy blocks………………...79

Table 3.2 Description of 158 chemotherapy blocks during which olanzapine was given

for CINV control…………………………………………………………………………80

Table 3.3 Description of olanzapine use during 158 chemotherapy blocks……………………..81

Table 3.4 Vomiting control and adverse events reported in 158 chemotherapy blocks

during which olanzapine was given……………………………………………………...82

List of Figures

The safety of olanzapine in young children: a systematic review and meta-analysis

Figure 2.1 Literature Search Flow Chart………………………………………………………...21

Figure 2.2 Forest Plots…………………………………………………………………………..22 2.2A Blood Glucose Abnormalities……………………………………………………...22 2.2B Electrocardiogram (ECG) Abnormalities…………………………………………..22 2.2C Extrapyramidal Symptoms…………………………………………………………23 2.2D Liver Function Test (LFT) abnormalities………………………………………….23 2.2E Sedation………………………………………………………………………….....24 2.2E Weight Gain………………………………………………………………………..24

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List of Abbreviations

5-HT3 Seretonin-3 ADHD Attention Deficit Hyperactivity Disorder AIMS Abnormal Involuntary Movement Scale ALP Alkaline phosphatase ALT Alanine aminotransferase ANC Absolute neutrophil count ASCO American Society of Clinical Oncology AST Aspartate aminotransferase BARF Baxter Retching Faces Scale BP Blood pressure BG Blood glucose BUN Blood urea nitrogen CBC Complete blood count CI Confidence interval CINV Chemotherapy-induced nausea and vomiting CIV Chemotherapy-induced vomiting CPK Creatinine phosphokinase CTCAE Common Terminology Criteria for Adverse Events CYP Cytochrome P450 ECG Electrocardiogram EEG Electroencephalogram EPS Extrapyramidal symptoms GEE Generalized estimating equations GI Gastrointestinal HR Heart rate K Potassium LDH Lactate dehydrogenase MASCC Multinational Association for Supportive Care in Cancer NCCN National Comprehensive Cancer Network NMS Neuroleptic malignant syndrome

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OR Odds ratio PeNAT Pediatric Nausea Assessment Tool PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses RCT Randomized-controlled trial

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Chapter 1: Introduction

1.1 Chemotherapy-induced Nausea and Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common, distressing adverse effects experienced by both children and adults receiving treatment for cancer with chemotherapy. It negatively influences the quality of life of children with cancer and can lead to clinical complications, such as dehydration and nutritional deficits, when it is not well controlled.1-5 For these reasons, complete prevention of CINV, defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention and no nausea-related change in the child’s usual appetite and diet, is the goal for all patients receiving chemotherapy.6

The pathophysiology of CINV is complex and the exact mechanism by which chemotherapy induces emesis and the sensation of nausea remains unknown. Areas in the central and peripheral nervous systems and gastrointestinal tract have been identified as important areas involved in the mediation of CINV.7 Specific mechanisms proposed include the release of serotonin following administration of chemotherapy which interacts with serotonin-3 (5-HT3) receptors on vagal afferent terminals. These fibers project to the dorsal vagal complex which houses multiple neurotransmitter receptors which may play an important role in the emetic response including neurokinin-1 (which binds to substance P), 5-HT3, dopamine-2, muscarinic, and histamine-1 receptors.7 These receptors are often the target of antiemetic agents used for the prevention and/or treatment of CINV.8 Efferent fibers from the dorsal vagal complex project to the central pattern generator which is the final effector of the emetic response. Chemotherapy may also induce emesis through interactions with the area postrema and structures in the temporal lobe including the amygdala.

There are multiple predictive factors which may assist clinicians in determining the likelihood that CINV may occur and its severity. These include chemotherapy emetogenicity, chemotherapy dose and patient-specific risk factors. The type of CINV patients may be at risk of developing is an additional important piece of information which may influence CINV prevention and treatment strategies.

Emetogenicity can be defined as the propensity of an agent to cause nausea, vomiting, or retching.9,10 Chemotherapy is generally classified as having minimal, low, moderate, or high emetic potential based on the frequency of emesis in the absence of effective prophylaxis. For example, chemotherapy defined as highly emetogenic is likely to cause emesis at a frequency greater than 90% when effective prophylaxis is not provided.9,11 The dose intensity of chemotherapeutic agents is one of the determining factors of emetogenic classification. For example, the same chemotherapeutic agent may be classified as having moderate or high emetogenic potential based on the dose being administered.

Multiple patient-specific risk factors for CINV have been identified in adult cancer patients including younger age (< 55 years of age), female sex, presence of anxiety or depression and a history of nausea and/or vomiting due to causes such as previous chemotherapy, pregnancy, surgery or motion sickness.4,12 Although age has also been raised as a possible risk factor for CINV in pediatric cancer patients the evidence is not conclusive.13,14 In fact, the inherent propensity of the chemotherapeutic agents administered, or each agents emetogenic potential, is the only factor known to be predictive of CINV in children.9

Distinct types of CINV have been defined relative to the time of chemotherapy administration. Examples of the different phases of CINV include acute CINV (begins with the administration of chemotherapy and continues for 24 hours after the last dose of chemotherapy is administered), delayed CINV (occurs more than 24 hours following the administration of chemotherapy and may persist for up to seven days after chemotherapy has been given), anticipatory CINV (occurs prior to the administration of chemotherapy), and breakthrough or refractory CINV (CINV occurring during the acute or delayed phase despite administration of CINV prophylaxis).6 The distinction between each type of CINV has important implications for prophylaxis. Since each is mediated via different pathways, each requires different modalities for successful control and treatment. For example, 5-HT3 is known to play an important role in acute CINV and 5-HT3 receptor antagonists are recommended for the prevention of CINV during this phase. In contrast, anticipatory CINV is thought to be a conditioned response which may involve a component of anxiety and therefore benzodiazepines, such as lorazepam, are recommended for the prevention of anticipatory CINV.

In summary, CINV is a complex issue and multiple factors must be taken into consideration when determining optimal prevention and treatment strategies.

1.2 Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting

Despite recent advances in antiemetic strategies, there are still limited options available for pediatric patients. In addition, only recently have pediatric-specific CINV prophylaxis guidelines been developed to assist with guiding clinical care for these patients.6,9,15 Agents currently recommended for the prevention of acute CINV in pediatric patients and considered the standard of care for most patients include 5-HT3 receptor antagonists (such as ondansetron or granisetron), corticosteroids (such as dexamethasone), and aprepitant (a neurokinin-1/substance P inhibitor) in patients greater than 12 years of age receiving chemotherapy not suspected to interact with this agent.6 These agents target neurotransmitter pathways involved in the mediation of CINV as described previously. Additional agents recommended in pediatric CINV guidelines include metoclopramide, nabilone, and chlorpromazine for the prevention of acute CINV and lorazepam for the prevention of anticipatory CINV.6,15

Antiemetic prophylaxis aims to completely prevent CINV. For chemotherapy-naïve children, CINV prophylaxis is based on the emetogenicity of the chemotherapy they are planned to receive. Other factors such as sex, age and alcohol use influence CINV risk in adults and may be used to select CINV prophylaxis in chemotherapy-naïve adult cancer patients.16 Once adult and pediatric cancer patients have received chemotherapy, CINV prophylaxis is individualized based on the patient’s history of CINV control, adverse effects of antiemetic agents, values and preferences. Antiemetics may also be added during a chemotherapy cycle to treat breakthrough CINV.

Unfortunately, many children are unable to achieve complete CINV control with the antiemetic strategies currently available. Specifically, it has been estimated that 50% of children receiving highly emetogenic chemotherapy and recommended antiemetics do not achieve complete control of CINV on days that chemotherapy is administered.6 Similarly, in a recently published pediatric

4 trial evaluating the efficacy of aprepitant, complete response, defined as no vomiting, no retching, and no use of rescue medication, ranged from 52% to 62% during the acute phase and 26% to 51% during the delayed phase.17 As the goal of antiemetic prophylaxis is complete prevention of CINV, these complete control rates are sub-optimal.

Poor CINV control may be due, in part, to a lack of evidence available to classify the emetogenic potential of chemotherapeutic agents used frequently in children and because there is little evidence evaluating patient-specific risk factors for CINV specifically in this population. Furthermore, there is little evidence to inform dosing of the available antiemetic agents in children and dosage forms suitable for pediatric patients are often unavailable. Therefore, children may frequently be prescribed antiemetic agents at inadequate doses and in dosage forms which preclude their administration. This may also partially explain why CINV control remains an issue for these patients. Large, comparative, randomized-controlled antiemetic trials have been conducted in adults to determine the safety and efficacy of antiemetic agents. Unfortunately these types of studies are not commonly done in the pediatric setting. Due to a delay in the availability of safety and efficacy information, routine use of antiemetics in children which have proven successful at improving CINV control in adults, such as palonosetron (a second generation 5-HT3 receptor antagonist) and aprepitant, is often delayed. For example, only recently was a randomized-controlled trial evaluating the use of aprepitant in children published.17 This agent was officially approved for use in adults by the Food and Drug Administration (FDA) in the United States in 2003 and by Health Canada in 2007. In addition, recommendations for its use have been incorporated into adult guidelines for CINV prevention since 2006.18

Overall, children have not seen the same benefits adults have regarding recent innovations in CINV prophylaxis. In order to optimize care for pediatric patients, new strategies to help prevent and control CINV are required and the evaluation of agents with proven efficacy in adults is a rational starting point. Olanzapine is an excellent example of one such option.

1.3 Olanzapine

Olanzapine is a second generation atypical antipsychotic agent of the thienobenzodiazepine class.19 It has activity at multiple neurotransmitter receptor sites and has been shown in vitro and in vivo to antagonize serotonin and dopamine induced responses.20-22 Although its exact mechanism of action is unknown, it is thought to mediate most of its effects via antagonism of these neurotransmitter receptor sites.

Olanzapine is highly metabolized by direct glucuronidation and cytochrome P450 mediated oxidation, primarily via CYP1A2 and CYP2D6.23 It is eliminated primarily in the urine (~57%) and to a lesser extent in the feces (~30%).24 The pharmacokinetics of olanzapine have been described in 8 children aged 10 to 18 years.25 The mean time to maximum olanzapine plasma concentration was 4.7±3.7 hours. The mean elimination half-life was 37.2 ± 5.1 hours. These values are similar to those observed in adult non-smokers. Another study evaluated the pharmacokinetic disposition of olanzapine in 22 patients aged 5 to 14 years (Eli Lilly Canada, personal communication, May 6, 2011). The mean and overall range of plasma olanzapine concentrations observed in these children were similar to adults when compared on the basis of the mg/kg dose administered.

Olanzapine is currently approved and indicated for the treatment of psychiatric conditions in adults in Canada, the United States and Europe. It is also approved for use in adolescents greater than 13 years of age in the United States for the treatment of schizophrenia or bipolar disorder.19 There is currently no approved indication for its use in children less than 13 years old for any indication, including CINV control, in any jurisdiction. Although initially developed for the purpose of treating psychiatric conditions, olanzapine has a broad pharmacological profile including activity at many of the receptors involved in the CINV pathway including dopamine and serotonin receptors as previously discussed in Chapter 1.1.26 As a result, it was identified as being worthy of rigorous evaluation for CINV control in adults. Similar to other agents used routinely in adults, it has not yet been adopted as a standard antiemetic agent in pediatric patients.

There have been multiple studies published regarding the use of olanzapine in adults for prevention and treatment of CINV including well-designed, large randomized-controlled trials.27-

36 Two systematic reviews were recently published which synthesized the results of these studies and summarized the efficacy of olanzapine for the prevention of CINV and the treatment of breakthrough or refractory CINV in adults.27,33 The review by Hocking et al. included 488 patients receiving olanzapine as prophylaxis and 323 patients receiving olanzapine for the treatment of breakthrough or refractory CINV. The authors of this review reported significant improvements in CINV prevention when olanzapine was administered in combination with additional antiemetics (including 5-HT3 receptor antagonists and dexamethasone) in comparison to aprepitant-containing antiemetic regimens. Olanzapine was also reported to be superior for the treatment of breakthrough CINV when compared to commonly used alternatives such as metoclopramide and prochlorperazine. Patients in all trials received a once daily 10mg dose of oral olanzapine for 3 to 5 days. No significant safety concerns were reported in any of the studies.

The review and meta-analysis completed by Wang et al., which included non-English papers that were excluded from the Hocking review, included 726 patients (including a large population of Chinese oncology patients) receiving olanzapine for prevention of CINV specifically. The relative risk of a complete response (defined as no vomiting and no use of rescue therapy) reported in this review was 4.07 (95% CI 1.59–10.43) which was significantly greater than that of standard therapy consisting of a 5-HT3 receptor antagonist plus a corticosteroid with or without a neurokinin-1 receptor antagonist (p = 0.003). Olanzapine was also reported to have superior anti-nausea effects compared with non-olanzapine regimens in the delayed and overall phases (OR = 2.79, 95% CI 1.76–4.43, p = 0.0001, and OR = 3.40, 95% CI 2.31–5.00, p = 0.00001, respectively).

Based on the results of the studies included in these systematic reviews and additional reports of its use in adult oncology, olanzapine is now recommended in adult antiemetic guidelines.18,37,38 For example, the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommend clinicians consider adding olanzapine to antiemetic regimens for patients experiencing breakthrough or refractory CINV.18,38 The Multinational Association for Supportive Care in Cancer (MASCC) also suggests olanzapine be considered as an option for breakthrough or refractory CINV. 37

At the time of initiation of the projects included in this thesis, there was no published evidence regarding the use of olanzapine for treatment or prevention of CINV in children. However, it was known anecdotally that olanzapine was being used off-label occasionally in children who had failed standard CINV prophylaxis.

1.4 Project Rationale and Purpose of Studies

The projects encompassed by this thesis were undertaken to provide a foundation to determine the value of evaluating the role of olanzapine as an antiemetic agent in pediatric oncology patients in the future.

The systematic review and meta-analysis were completed to summarize the adverse effects of olanzapine use in young children with the intention of determining whether or not any safety concerns would preclude further investigation of its use as an antiemetic agent in children. This was completed specifically in children younger than 13 years of age as this is the age for which there is no licensed indication for the use of olanzapine. The aim of a systematic review is to identify, evaluate, and summarize the findings of all relevant individual studies regarding a health-related issue (in this instance the safety of olanzapine) to help inform and facilitate healthcare decisions based on the best available evidence.39 Completion of a systematic review was felt to be a logical first step as no evidence regarding the use of olanzapine in pediatric cancer patients was available. Although direct extrapolation from the safety of olanzapine in children for non-oncology indications has limitations, a comprehensive summary of its safety in children less than 13 years old was considered a reasonable starting point.

The retrospective, multi-center review was completed as a baseline assessment of the current status of the clinical use of olanzapine for CINV control in pediatric cancer patients, with the primary aim being an evaluation of the efficacy and safety of its use in this population. Although we were aware of the use of olanzapine as an antiemetic agent in children at our institution, we were interested in learning about the experience of other centers in North America regarding the use of olanzapine for CINV in children and in formally summarizing these experiences. Before designing a larger, controlled trial, a review of how olanzapine was being used in practice was essential.

Chapter 2: The Safety of Olanzapine in Young Children: A Systematic Review and Meta-Analysis

The contents of this chapter have been published in Drug Safety and are included in this thesis with permission of Springer Science + Business Media: Flank J, Sung L, Dvorak CC, Spettigue W, Dupuis LL. The safety of olanzapine in young children: a systematic review and meta- analysis. Drug Safety. 2014 October; 37(10): 791-804. E-pub August 2014. Copyright 2014 by Springer Science + Business Media.

All authors were involved in conception and planning of the work that led to development of this manuscript as well as revisions of all drafts and approval of the final draft submitted for publication.

In addition to acting as the primary author of this manuscript, I was involved in completion of the literature search (with the assistance of a library scientist) and review of all articles for inclusion/exclusion (including title and abstract screening and full-text screening). I extracted data from all included articles and summarized this information in evidence tables. I assessed the risk of bias of all included studies independently from an additional author and was responsible for comparing our assessments. The meta-analysis was initially completed by Lee Dupuis (supervisor). I reviewed these results and went through the process of how the meta- analysis was done with Lee Dupuis to ensure understanding of the methods, how to use the software (including RevMan software), and as a learning opportunity should I wish to conduct similar projects in the future. The systematic review and meta-analysis were completed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) reporting guidelines. 40,41

2.1 Abstract

Background: Olanzapine is frequently prescribed in young children for psychiatric conditions. It may be an option for chemotherapy-induced nausea and vomiting (CINV) control in children. The objective of this review was to describe the safety of olanzapine in children less than 13 years of age to determine if safety concerns would be a barrier to its use for CINV prevention. Methods: Electronic searches were performed in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and Scopus. All studies in English reporting adverse effects associated with olanzapine use in children younger than 13 years or with a mean/median age less than 13 years were included. Adverse outcomes were synthesized for prospective studies. Results: A total of 47 studies (17 prospective) involving 387 children aged 0.6–18 years were included; nine described olanzapine poisonings. Weight gain or sedation were reported in 78 % [95 % confidence interval (CI) 63–95] and 48 % (95 %CI 35–67), respectively. Extrapyramidal symptoms or electrocardiogram abnormalities were reported in 9 % (95 % CI 4–21) and 14 % (95 % CI 7–26), respectively. Elevation in liver function tests or blood glucose abnormalities were reported in 7 % (95 % CI 2–20) and 4 % (95 % CI 1–17), respectively. No deaths were attributed to olanzapine. No studies were identified with a primary focus on evaluating safety, and the adverse effects reported in the included studies were heterogeneous. Conclusions: Most adverse events associated with olanzapine use in children less than 13 years of age are of minor clinical significance. These findings support the exploration of olanzapine for the prevention of CINV in children in future trials.

2.2 Introduction

Olanzapine is an atypical antipsychotic agent that is approved for use in the USA in patients greater than 13 years of age with psychiatric conditions. There is currently no approved indication for its use in patients less than 18 years of age in Canada and Europe. Nevertheless, olanzapine is frequently prescribed off-label for the treatment of various psychiatric and behavioural disorders in children.42-45 Adverse effects associated with olanzapine in adults include weight gain, sedation, extrapyramidal symptoms (EPS), abnormalities in liver function

10 tests (LFTs) and increased blood glucose, prolactin, cholesterol and/or triglyceride concentrations.19 Adolescents receiving olanzapine may be at increased risk of experiencing some of these adverse effects, including weight gain, increased body mass index, and elevated blood glucose, cholesterol, triglyceride and prolactin concentrations.46-48 The adverse effect profile of olanzapine in younger children has not been described systematically.

Olanzapine has recently shown promising results for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in adult cancer patients.27,28,30,31,34 Its efficacy can be attributed to its activity at many of the receptor sites involved in the mediation of CINV, including serotonin and dopamine pathways. Despite advances in antiemetic strategies for pediatric cancer patients, children receiving chemotherapy continue to experience uncontrolled CINV, which may limit their quality of life and lead to associated clinical problems.2,6 Olanzapine may be a valuable option for the prevention and treatment of CINV in children on the basis of its success in adults.

There are currently no published studies evaluating the use of olanzapine for prevention or treatment of CINV in children. Before undertaking future trials to evaluate the use of olanzapine for CINV control in children, a review of the adverse effects reported with olanzapine use in young children would be useful. The objective of this study was to describe the adverse effects associated with olanzapine use in children less than 13 years of age, the age at which the use of olanzapine is off-label in the USA.

2.3 Methods

2.3.1 Search Strategy and Data Sources

With the assistance of a library scientist, we conducted electronic searches of the following databases: OVID MEDLINE (1946–May 21, 2014), EMBASE and EMBASE Classic (1947– week 20, 2014), Cochrane Central Register of Controlled Trials (2005–April 2014), Web of Science (accessed May 21, 2014), and Scopus (accessed May 21, 2014). The search was completed in September 2013 and updated May 21, 2014. The complete search strategy is presented in Table 2.1. The search was limited to studies including infants, children and

11 adolescents and those published in English. There was no restriction by study design. Reference lists of pertinent publications, including review articles, were searched to ensure all relevant articles meeting our inclusion criteria were included.

2.3.2 Study Selection

The following inclusion criteria were applied to the studies identified: (1) the population included patients younger than 13 years of age (either results were reported separately for patients younger than 13 or the mean or median age of participants was less than 13 years); (2) the study described adverse effects associated specifically with the use of olanzapine; and (3) the dose of olanzapine used or, in the case of poisoning where the dose ingested was not able to be determined, a blood olanzapine concentration was reported. The exclusion criteria were (1) not published in English, (2) conference abstracts or proceedings, (3) not a primary study (for example, reviews and editorials), (4) adverse effects not described, (5) specific results for olanzapine not reported separately from those of other medications, (6) population did not consist of children younger than 13 years of age or the mean or median age of participants was ≥13 years, and (7) duplicate studies. Duplicate studies were identified electronically using EndNote X7.1 (Bld 7705; Thomson Reuters); one reviewer (JF) reviewed all citations with the same title and/or authors to ensure removal of duplicate publications. Papers describing infants who were exposed to olanzapine in utero or via breast milk were also excluded.

The titles and abstracts of all studies identified were screened by two reviewers (JF and LD). Primary articles which described the use of olanzapine in children in the title and/or abstract were selected for full-text screening. Studies that proceeded to full-text screening were reviewed by two individuals (JF and LD). All discrepancies were discussed, and final inclusion of studies was based on agreement of both reviewers. An inter-rater reliability analysis using the Kappa statistic was performed to determine consistency among screeners (SAS Institute Inc.; Cary, NC, USA).

Study designs included randomized controlled trials, prospective single-blind, open-label, and naturalistic studies, retrospective reviews, case series and case reports. Included studies were divided into those evaluating the use of olanzapine at usual recommended doses and studies

12 focusing on overdose with olanzapine. Studies administering olanzapine at usual doses were divided into prospective versus non-prospective studies; only prospective studies were considered for synthesis.

2.3.3 Data Collection Process and Quality Assessment

Data were extracted from included studies by one reviewer (JF) and verified by an additional reviewer (LD). All included studies published by the same author(s) were reviewed to ensure data which may have been reported in multiple publications were included only once in our review and meta-analysis. Information gathered from each study included the study design, study aim, patient characteristics (sample size, age, gender, and indication for olanzapine use), dose of olanzapine used (in mg/kg/dose if reported or calculable and including the titration schedule if applicable), length of treatment with olanzapine, adverse effects monitored (including frequency and tools for monitoring), and adverse effects reported by the authors. Information was included on any adverse effects reported by the authors with a focus on those effects for which a proportion of patients who experienced the adverse effect was reported or could be calculated. Information was also gathered for changes from baseline in safety parameters which were statistically or clinically significant, including laboratory values monitored, with a focus on those values falling outside the normal range reported for age. Where available, information was collected for comparative groups when studies included either a placebo or different medication arm. Additional information was gathered for those articles describing olanzapine overdose, including the olanzapine blood concentration (if reported), other medications ingested, clinical presentation, and treatment and follow-up.

An effort was made to contact one author via e-mail to obtain more detailed information regarding adverse effects described in a supplementary table which was no longer available electronically. A response was not received. The available information related to adverse effects from this article was incorporated into the review and meta-analysis.49

The risk of bias of included studies other than case reports was assessed independently by two reviewers (JF and LD) using a modified tool initially developed to describe the quality of

13 prognostic studies.50 Discrepancies were discussed and the final assessment was assigned on the basis of the agreement of both reviewers. A focus was placed on the risk of bias in outcome measurement, which may have most influenced adverse effect reporting. Each study was rated as having a low, medium, or high risk of bias in measurement of adverse effects. The cumulative reported incidence of adverse effects that were not included in the meta-analysis (see below) but that were evaluated in at least three prospective studies was calculated.

2.3.4 Meta-Analysis

The proportion of patients who were reported to have experienced adverse effects which were assessed objectively [e.g. change in body weight, change in laboratory values, echocardiogram (ECG) abnormalities and EPS] or which have been reported to be commonly observed in adolescents (weight gain and sedation) were synthesized using Review Manager (RevMan Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). The meta-analysis was limited to prospective studies including randomized controlled trials and open-label studies; retrospective reviews, case series and case reports were not included in this analysis since identification and measurement of adverse effects in these studies were subject to a high risk of bias. Outcomes were synthesized if at least two studies reported data on that outcome. Data were synthesized using proportions of children reported in each study to have experienced the adverse effect in question. Since proportions were not distributed normally, syntheses were conducted using the natural logarithm of the proportion as the outcome. Differences in mean proportion based on study design were evaluated using χ2; p < 0.05 was considered to be significant.

2.4 Results

Figure 2.1 depicts the studies identified, screened, deemed eligible for inclusion and ultimately included in this review. A total of 4,238 articles were identified during the literature search. After abstract and title screening, 191 full-text articles were reviewed. Of these, 47 studies met inclusion criteria: 38 studies (17 prospective studies) evaluated olanzapine at usual recommended doses and nine studies described olanzapine overdose. Agreement between

14 reviewers for inclusion of articles was almost perfect [kappa = 0.97, 95 % confidence interval (CI) 0.93–1.00]. Table 2.2 describes the characteristics of all the included studies.

2.4.1 Therapeutic Use of Olanzapine: Prospective Studies

The risk of bias in outcome measurement in the included studies is summarized in Table 2.2 and is highly variable. Safety assessment was a secondary outcome in all included studies; some relied exclusively on spontaneous reporting of adverse effects during the period of time that olanzapine was administered, while others relied on specific tools to screen for specific possible adverse effects. Table 2.3 summarizes the information gathered from the randomized controlled trials (2)49,51, prospective studies (15)52-66, and retrospective reviews (2)67,68.

A total of 254 patients, aged 4–17.9 years, participated in the included prospective studies. The indication for olanzapine use was for treatment of a psychiatric, developmental, or behavioural disorder. The duration of olanzapine use ranged widely (11.3 days to over 1 year), but the majority of studies (13/17) reported durations between 6 and 12 weeks. The dose of olanzapine used in the studies was often titrated on the basis of efficacy and patient tolerability and ranged from 1.25 to 20 mg daily. The olanzapine dose range was not reported in one study.

Twenty patients were reported to have withdrawn from the olanzapine arms of the prospective studies. Adverse effects attributed to olanzapine prompted the withdrawal of seven patients. Four patients withdrew because of weight gain, while the following adverse effects prompted the withdrawal of a further three patients: increased appetite (one patient), tremor (one patient), and increased appetite and hand tremor (one patient).

Data regarding sedation (12 studies), weight gain (seven studies), EPS (12 studies), ECG abnormalities (five studies), LFT abnormalities (three studies) and blood glucose abnormalities (three studies) were synthesized. The number of studies which reported the proportion of patients with other laboratory value abnormalities [i.e. elevations in plasma prolactin (one study), cholesterol (one study) and/or triglyceride concentrations (no studies)] was too few to permit synthesis.

The findings of the meta-analysis are summarized in Table 2.4 and Figure 2.2. There was no difference in mean proportion between randomized controlled studies and other prospective studies (p>0.05). Sedation and weight gain were reported in 48 % (95 % CI 35–67) and 78 % (95 % CI 63–95) of children, respectively. Other adverse effects reported to be more common in adolescents were less common in children less than 13 years of age. Abnormalities in blood glucose and LFT results were less commonly reported: 4 % (95 % CI 1–17) and 7 % (95 % CI 2– 20), respectively.

EPS was evaluated using tools such as the Abnormal Involuntary Movement Scale (AIMS), Tardive Dyskinesia Rating Scale, Barnes Akathisia Score, and Simpson Angus Scale. EPS was reported in 9 % (95 % CI 4–21) of children. Of the four studies in which EPS was observed53,55,59,61, symptoms of EPS were immediately reversed after treatment with benztropine in one study, and a second reported that this adverse effect disappeared after patients’ olanzapine doses were decreased55,61. The other two studies do not provide details of the EPS symptoms or their management.

ECG was obtained in 64 children at baseline and during olanzapine therapy, and abnormalities were reported in 7 % (95 % CI 7–26). Three studies reported the details of ECG abnormalities. One patient had multiple atrial premature complexes and was deemed fit to continue receiving olanzapine treatment after consultation with cardiology.49 In the second study, two patients experienced ECG abnormalities which were not thought to be caused by olanzapine.58 One patient had sinus tachycardia thought to be a result of agitation; the second had apparent ventricular hypertrophy at the baseline assessment which resolved over the course of the study. Kemner et al. observed ECG abnormalities in four patients which were not deemed to be clinically relevant or which were transient.55 None of these seven patients exhibited QTc prolongation.

Table 2.5 summarizes the cumulative reported incidence of adverse effects that were not included in the meta-analysis. Of these adverse effects, cold or flu-like symptoms, constipation, other gastrointestinal problems, and headache were most commonly reported. No fatal events attributed to olanzapine were reported.

2.4.2 Therapeutic Use of Olanzapine: Retrospective Reviews

Two retrospective reviews were included in this review, both of which are summarized in Table 2.2 and Table 2.3. These reviews included a total of 94 patients aged 0.6–18 years receiving olanzapine for the treatment of delirium. Patients included in these studies received olanzapine for anywhere from 1 to 151 days at doses ranging from 0.5 to 60 mg/day. In both studies, only one patient was reported to have experienced dystonia, which resolved when the olanzapine dose was decreased. No cardiac arrhythmias, EPS, or metabolic syndrome related adverse effects were reported. No fatal events attributed to olanzapine were reported.

2.4.3 Therapeutic Use of Olanzapine: Case Reports and Case Series

Table 2.6 summarizes the data collected from case reports and case series which met inclusion criteria.69-87 The age of the 30 patients included in these reports ranged from 4.25 to 12 years. Similar to the previously described studies, most patients received olanzapine for the management of behavioural or psychiatric conditions. The olanzapine dose administered in these reports ranged from 1.25 to 20 mg daily. The treatment duration, reported only by nine of the 19 authors, ranged from a few days to several months.

Similar to the findings of the meta-analysis, weight gain (15 patients) and sedation (six patients) were commonly reported. Two authors each reported a single case of a serious potential adverse effect potentially associated with olanzapine use: catatonia and neuroleptic malignant syndrome (NMS).72,74 Olanzapine was not felt to be the causal factor for catatonia by the authors of the first study as this patient did not present with the usual expected symptoms associated with antipsychotic-induced catatonia (dystonia, tremor, tardive dyskinesia, and/or fever). The patient who experienced olanzapine-associated NMS also experienced NMS following the administration of other atypical antipsychotics (risperidone and quetiapine). After all antipsychotics were discontinued, NMS symptoms resolved without long-term complications.

2.4.4 Olanzapine Overdoes/Poisoning: Case Reports

Data extracted from the case reports of olanzapine overdose for nine patients are summarized in Table 2.7.88-96 Patients ranged in age from 1 to 12 years, and the olanzapine doses ingested ranged from 7.5 to 100 mg. The ingested dose was unknown for one patient; however, an olanzapine blood concentration was reported as 340 ng/mL 5 h post-ingestion. The olanzapine blood concentration was reported for an additional six patients (11–888 ng/mL) and varied depending on the timing of the concentration in relation to ingestion of olanzapine. For comparison, plasma olanzapine concentrations usually range from 5 to 75 ng/mL in adults receiving therapeutic doses.97 The most frequent adverse effects associated with olanzapine overdose were drowsiness/lethargy/somnolence (8/9 patients), agitation/combativeness (7/9 patients) and tachycardia (6/9 patients). There were no fatal events attributed to olanzapine. Only one patient had sequelae at follow-up: a 9-year-old, 29-kg boy who ingested 100 mg of olanzapine had a ‘‘slight’’ upper extremity tremor at 13 days post-ingestion, which had improved significantly from the patient’s initial presentation. There was no further follow-up for this patient.

2.5 Discussion

In this systematic review, we found that the most common adverse events attributed to olanzapine were weight gain and sedation. Potentially serious adverse events were either not attributed to olanzapine and/or were reversible. No deaths were attributed to olanzapine in children. Consequently, neither the incidence of reported adverse effects nor their clinical severity presents barriers to the future evaluation of olanzapine for the prevention of CINV in young children.

We identified 47 studies that reported adverse effects associated with olanzapine in 387 children younger than 13 years of age. In order to accurately describe the contribution of olanzapine to adverse events, randomized controlled trials are the best design. However, only two included studies were randomized, which makes it more difficult to attribute the adverse events reported to olanzapine specifically. Although of lesser quality than randomized controlled trials, the

18 prospective studies included in this review reported important and detailed information about adverse effects experienced by patients.

Synthesis was completed for those adverse effects objectively evaluated or most commonly reported in adolescents: ECG abnormalities, EPS, LFT abnormalities, blood glucose abnormalities, sedation and weight gain.

Mirroring the experience in adolescents, olanzapine-associated sedation and weight gain were commonly reported. However, blood glucose and LFT abnormalities were fairly uncommon. With respect to weight gain, it is important to note that patients included in the studies where weight gain was reported received olanzapine for at least 6 weeks. There appears to be a temporal relationship between use of olanzapine and weight gain, with risk increasing with duration of treatment. The most significant increase in weight (mean 12.8 kg) was reported for patients taking olanzapine for 1 year.62 These results are not surprising considering the numerous reviews that describe the association between olanzapine and weight gain in older children.46,98

Although concerning when they do occur, serious adverse effects associated with olanzapine seem to be uncommon. Nevertheless, it is important that children, parents and care-providers are taught to recognize the symptoms of EPS and NMS before a course of olanzapine is initiated.

The retrospective reviews of olanzapine use in young children provided an opportunity to observe the use of olanzapine in unique populations since they included patients as young as 7 months of age and receiving doses of olanzapine up to 60 mg daily. However, because of their retrospective design, very little detailed information regarding adverse effects associated with olanzapine were available, and attributing causality of the reported adverse effects is challenging. Nevertheless, the adverse effects reported in the retrospective reviews are reassuring considering the wide variability in patient age and olanzapine dose in these studies.

Although little high quality information could be gathered from the case reports included, they provide examples of the use of olanzapine in children younger than 13 years at therapeutic doses. Case reports describing the symptoms and management of children after olanzapine overdose

19 provide a description of the extremes of dose-related olanzapine toxicity in very young children. Of importance, eight of the nine patients in the case reports included made a complete recovery after overdose and no long-term complications were reported for these patients. Meli et al. recently described the acute toxicity profile of four atypical antipsychotic agents, including olanzapine, in young children, using poison center data.99 Specific doses of olanzapine ingested or blood concentrations were not reported by the authors; therefore, this study was excluded from our review. Nevertheless, the authors report a ‘‘toxic dose’’ threshold of 0.4 mg/kg, above which patients were noted to experience ataxia and somnolence. The most commonly reported symptom associated with olanzapine intoxication was minor reduction in vigilance (defined as a Glasgow Coma Score of >9). Of note, no patients were reported to have experienced QTc prolongation or EPS.

It is important to note that in considering the use of olanzapine in pediatric cancer patients, none of the studies included in this review administered the drug concurrently with chemotherapy. Consequently, nothing is known from these studies about the potential for interactions with chemotherapy or pediatric cancer supportive care drugs, or whether there are unique toxicities in this particular patient population. We are cautious regarding our ability to extrapolate the findings of this systematic review to the use of olanzapine in pediatric cancer patients since our findings may not be applicable to pediatric cancer patients who receive olanzapine for CINV control. Patients described in the studies included in this systematic review often received olanzapine over a number of weeks and the doses were usually titrated to an optimal dose. Children receiving olanzapine for the prevention of CINV would receive the medication over no more than several days while they receive blocks of chemotherapy. We cannot be certain that patients would tolerate a dose that has not been titrated. However, it is possible that sedation and weight gain may actually be viewed in a positive light in children receiving chemotherapy that is otherwise associated with anorexia and weight loss. Future feasibility or early phase studies are required to evaluate the safety of olanzapine in pediatric oncology patients.

The strength of this report is the systematic review of published reports of the adverse effects of olanzapine in young children. This knowledge is important to allow and plan future trials of olanzapine. The adverse effects identified in this review should be specifically monitored in prospective trials conducted in pediatric cancer patients.

Potential limitations to this systematic review must be considered. No studies were conducted specifically in this age group with a primary focus on evaluating safety. For this reason, less stringent inclusion/exclusion criteria were applied when determining study eligibility in our systematic review so as to capture all potential adverse effects reported as secondary outcomes. The heterogeneity of the adverse effects reported in the included studies limited our ability to synthesize the incidence of many possible adverse effects of olanzapine use. However, we believe that the summary of case reports of the therapeutic use of olanzapine as well as case reports of poisoning provide information regarding possible rare or dose-related toxicities. We acknowledge that case reports and case series may be subject to publication bias. There are additional limitations associated with the study inclusion/exclusion criteria chosen. Based on our age restriction and by only including studies where the mean or median age was less than 13 years, we may have missed descriptions of the experience of those patients younger than 13 years included in studies where the mean or median age exceeded 13 years. Although our literature search was comprehensive, only articles published in English were included and we may have missed relevant publications printed in other languages.

2.6 Conclusions

Overall, the use of olanzapine in children younger than 13 years appears relatively safe when it is administered at doses ranging from 2.5 to 20 mg and titrated to patient tolerability. Adverse effects such as sedation and weight gain may not be a large concern when used for short periods of time in pediatric cancer patients. On the basis of these findings and the drug’s success as an antiemetic agent in adult cancer patients, future exploration of the efficacy of olanzapine for the prevention and/or treatment of CINV in children is warranted. Such evaluations should use rigorous methods and involve the use of validated pediatric tools for the assessment of nausea in order to determine efficacy. Standardized and, when possible, objective approaches should be used to evaluate the safety of olanzapine in pediatric cancer patients who may receive this medication for CINV.

Figure 2.1 Literature Search Flow Chart

Figure 2.2 Forest Plots

2.2A Blood Glucose Abnormalities

2.2B Electrocardiogram (ECG) Abnormalities

2.2C Extrapyramidal Symptoms

2.2D Liver Function Test (LFT) Abnormalities

2.2E Sedation

2.2F Weight gain

Table 2.1 Complete Search Strategy

MEDLINE(R) 1946 to Present with Daily Update (Sept 30, 2013)

1. (Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or "ly170053" or meltolan or midax or olace or oladay or olan or olandus or olanex or olansek or olapin or olazax or oleanz or olexar or oltal or olzap or onza or "ozapin md" or psychozap or relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav).mp.

2. (infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or pediatric*).mp.

3. 1 and 2

4. limit 3 to English language

5. limit 1 to ("newborn infant (birth to 1 month)" or "infant (1 to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to 12 years)")

6. limit 5 to English language

7. 4 or 6

Embase Classic+Embase 1947 to 2013 Week 39

1. olanzapine/

2. limit 1 to (infant or child or preschool child <1 to 6 years> or school child <7 to 12 years>

3. limit 2 to English language

4. (Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or "ly170053" or meltolan or midax or olace or oladay or olan or olandus or olanex or olansek or olapin or olazax or oleanz or olexar or oltal or olzap or onza or "ozapin md" or psychozap or relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav).tw.

5. (infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or pediatric*).mp.

6. 4 and 5

7. limit 6 to English language

8. 3 or 7

Table 2.1 Continued Complete Search Strategy

Cochrane Central Register of Controlled Trials August 2013 (CENTRAL) Database of Abstracts of Reviews of Effects 3rd Quarter 2013 Reviews 2005 to August 2013

2. (infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or pediatric*).mp.

3. 1 and 2

Web of Science Science Citation Index Expanded (SCI-EXPANDED) --1900-present Social Sciences Citation Index (SSCI) --1956-present Conference Proceedings Citation Index- Science (CPCI-S) --1990-present Conference Proceedings Citation Index- Social Science & Humanities (CPCI-SSH)-1990-present

# 4 #2 AND #1

Refined by: Languages=( ENGLISH )

Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years

# 3 #2 AND #1

Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years

# 2 TS=(infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or pediatric*)

Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years

# 1 TS=(Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or "ly170053" or meltolan or midax or olace or oladay or olan or olandus or olanex or olansek or olapin or olazax or oleanz or olexar or oltal or olzap or onza or "ozapin md" or psychozap or relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav)

Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years

Table 2.1 Continued Complete Search Strategy

SCOPUS

(TITLE-ABS-KEY(olanzapine) OR TITLE-ABS-KEY(anzatric) OR TITLE-ABS-KEY("dopin tab") OR TITLE-ABS-KEY("jolyon md") OR TITLE-ABS-KEY(lanopin) OR TITLE-ABS- KEY(lanzac) OR TITLE-ABS-KEY("ly 170053") OR TITLE-ABS-KEY("ly170053") OR TITLE-ABS-KEY(meltolan) OR TITLE-ABS-KEY(midax) OR TITLE-ABS-KEY(olace) OR TITLE-ABS-KEY(oladay) OR TITLE-ABS-KEY(olan) OR TITLE-ABS-KEY(olandus) OR TITLE-ABS-KEY(olanex) OR TITLE-ABS-KEY(olansek) OR TITLE-ABS-KEY(olapin) OR TITLE-ABS-KEY(olazax) OR TITLE-ABS-KEY(oleanz) OR TITLE-ABS-KEY(olexar) OR TITLE-ABS-KEY(oltal) OR TITLE-ABS-KEY(olzap) OR TITLE-ABS-KEY(onza) OR TITLE- ABS-KEY("ozapin md") OR TITLE-ABS-KEY(psychozap) OR TITLE-ABS-KEY(relprevv) OR TITLE-ABS-KEY(zalasta) OR TITLE-ABS-KEY(zelta) OR TITLE-ABS-KEY(zydis) OR TITLE-ABS-KEY(zypadhera) OR TITLE-ABS-KEY(zyprex) OR TITLE-ABS-KEY(zyprexa) OR TITLE-ABS-KEY(zyprexav)) AND (TITLE-ABS-KEY(infan*) OR TITLE-ABS- KEY(neonat*) OR TITLE-ABS-KEY(child*) OR TITLE-ABS-KEY(girl*) OR TITLE-ABS- KEY(boy*) OR TITLE-ABS-KEY(tot) OR TITLE-ABS-KEY(tots) OR TITLE-ABS- KEY(toddler*) OR TITLE-ABS-KEY(paediatric*) OR TITLE-ABS-KEY(pediatric*)) AND (LIMIT-TO(LANGUAGE, "English"))

Table 2.2 Characteristics of Included Studies Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 10±2.04mg/day Hollander 2006 RCT Moderate 6 9.25±2.9yrs Pervasive developmental (7.5-12.5mg/day) 8 weeks disorder (6-14.8yrs) 18.1±4.3mg/day Shaw 2006 RCT Low 13 12.8±2.4yrs Childhood-onset (5-20mg/day) 8 weeks schizophrenia (6-17yrs) 8.6±3.4mg/day Wozniak 2009 Prospective, Moderate 17 10.2±2.6yrs Bipolar disorder (olanzapine group) 8 weeks open-label (7.5-12.5mg/day) comparison (6-17yrs) 7.5mg/day Fido 2008 Prospective, Moderate 40 12.2±2.2yrs Autism (5-10mg/day) 13 weeks open-label (7-17yrs) 11.3±5.6mg/day McCracken 2008 Prospective, Moderate 12 11.33±2.35yrs Tourette syndrome (2.5-20mg/day) 6 weeks open-label (7-14yrs) 6.8±6.41mg/day (female Quintana 2007 Prospective, Moderate 16 12.9±2.48yrs Schizophrenia participants) 9 weeks open-label 8.33±4.51mg/day (male (8-17.9yrs) participants) (2.5-20mg)

8.25mg/day Milin 2006 Prospective, Moderate 10 12.6±2.02yrs Asperger disorder (5-15mg/day) 12 weeks open-label (10-15yrs)

Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 8.18±4.41mg/day Mozes 2006 Prospective, Low 12 11.5±1.64yrs Childhood-onset (2.5-20mg/day) 12 weeks open-label schizophrenia comparison (9-14yrs) 5.8mg/day Sethi 2006 Prospective, High 6 median: 9yrs Sydenham chorea (5-10mg/day) 3-4 months open-label (5-13yrs) 6.3±2.3mg/day Biederman 2006 Prospective, Moderate 15 5±0.8yrs Bipolar disorder (1.25-10mg/day) 8 weeks open-label comparison (4-6yrs) 14.5mg/day Stephens 2004 Prospective, Moderate 10 9.9±1.7yrs Tourette syndrome (1.25-20mg/day) 8 weeks open-label (7-13yrs) 15.56±4.64mg/day Mozes 2003 Prospective, Moderate 9 12.5±1.13yrs Childhood-onset (10-20mg/day) 10 weeks open-label schizophrenia (11-14yrs) 5.1±2.2mg/day (week 3) Ross 2003 Prospective, Moderate 19 10.5±2.4yrs Childhood-onset 6.1±3.6mg/day (week 6) Up to 1 year open-label Schizophrenia 7.7±4.1mg/day at (3 (6-15yrs) months) 9.3±4.7mg/day (6 months) 10.4±3.5mg/day (1 year)

10.7mg/day Kemner 2002 Prospective, Moderate 25 mean: 11.22yrs Pervasive developmental (2.5-20mg/day) 12 weeks open-label disorder (6.4-16.6yrs) 9.6±4.3mg/day Frazier 2001 Prospective, Moderate 23 10.3±2.9yrs Acute mania (2.5-20mg/day) 8 weeks open-label (5.4-14.7yrs)

Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 7.9±2.5mg/day Malone 2001 Prospective, High 6 8.5±2.4yrs Autism (5-10mg/day) 6 weeks open-label comparison (4.9-11.8yrs) 4.8mg/day Sholevar 2000 Prospective, High 15 9.4±1.99yrs Childhood-onset (2.5-5mg/day) Mean: 11.3 open-label schizophrenia days (6-13yrs) 4.81±5.76mg/day Mean: 39±41.4 Turkel 2013 Retrospective High 16 1.7±0.67yrs Delirium (0.5-23mg/day) days review (0.58-2.8yrs) (Range: 2- 151days) 10mg/day Mean: 26.5 Turkel 2012 Retrospective High 78 10.8±4.9yrs Delirium (0.625-60mg/day) days review (1-18yrs) (Range: 1- 132days) 15mg/day Taskiran 2013 Case report N/A 1 7.5yrs Pervasive developmental 2 months disorder 5mg/day Bozkurt 2010 Case report N/A 1 11yrs Catatonia Not reported 2.5-7.5mg/day Herguner 2010 Case report N/A 1 6yrs Autistic disorder Not reported 15mg/day Ferreira Maia 2007 Case report N/A 1 10yrs Bipolar disorder Not reported 15mg/day Emiroglu 2006 Case report N/A 1 8yrs Bipolar disorder 6 months

Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 8.75mg/d (↓ to Beresford 2005 Case report N/A 1 4.25yrs Schizophreniform 3.75mg/day after 1 Not reported disorder month)

2.5mg/day Chungh 2005 Case report N/A 1 12yrs Bipolar disorder and mild 2 days mental retardation 2.5mg/day Courvoisie 2004 Case report N/A 1 7yrs Attention deficit Approx. 9 hyperactivity disorder, months bipolar disorder, and oppositional defiant disorder 5-15mg/day Ercan 2004 Case report N/A 1 12yrs Schizophrenia Not reported 2.5mg/day Boachie 2003 Case series N/A 4 11yrs Anorexia nervosa Not reported

(10-12yrs) 2.5-7.5mg/day Sheikh 2002 Case report N/A 1 10yrs Acute agitation and 15 days attention deficit hyperactivity disorder 5mg/day Mehler 2001 Case report N/A 1 12yrs Anorexia nervosa Not reported 5mg/day Nguyen 2001 Case report N/A 1 10yrs Attention deficit Several months hyperactivity disorder (specific time frame not reported)

Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 5mg/day, increased to Bengi Semerci 2000 Case report N/A 1 9yrs Tourette’s disorder 10mg/day after one week Not reported 2.5-5mg/day Chang 2000 Case series N/A 3 10.3yrs Acute mania 1-3months

(9-12yrs) 1.25-2.5mg/day Lavid 1999 Case reports N/A 2 9.5yrs Stuttering 2-5mths

(9-10yrs) 7.5mg/day Krishnamoorthy 1998 Case series N/A 5 9.2yrs Psychiatric disorder (2.5-10mg/day) 14-52 days

(6-11yrs) 5-7.5mg/day Malek-Ahmadi 1998 Case report N/A 1 8yrs Hyperactivity and Not reported aggressive behaviour 5-20mg/day Horrigan 1997 Case reports N/A 2 9.5yrs Bipolar disorder, mental Not reported retardation, and autistic (9-10yrs) behaviour 75-100mg Hail 2013 Case report N/A 1 6yrs Not applicable Not applicable (overdose) 20-50mg Tanoshima 2013 Case report N/A 1 1.4yrs Not applicable Not applicable (overdose) Reported: 30mg Lankheet 2011 Case report N/A 1 2.3yrs Not applicable Estimated based on Not applicable (overdose) levels: 115-230mg 210mg Kochhar 2002 Case report N/A 1 12yrs Not applicable Not applicable (overdose)

Author Year Study Design Risk of Bias in N Mean Age ± Diagnosis Mean Olanzapine Dose Duration of Pub Measurement of Standard ± Standard Deviation Olanzapine Adverse Effects Deviation (range) Treatment (range ) 10mg Bond 1999 Case report N/A 1 6yrs Not applicable Not applicable (overdose) Unknown Bonin 1999 Case report N/A 1 1yr Not applicable (level = 340ng/mL) Not applicable (overdose) 30-40mg Catalano 1999 Case report N/A 1 1.5yrs Not applicable Not applicable (overdose) 100mg Chambers 1998 Case report N/A 1 9yrs Not applicable Not applicable (overdose) 7.5-15mg Yip 1998 Case report N/A 1 2.5yrs Not applicable Not applicable (overdose)

N: Number, N/A: not applicable, RCT: Randomized-controlled trial

Table 2.3 Summary of Randomized Controlled Trials, Prospective Studies, and Retrospective Reviews

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Randomized Controlled Trials

Hollander Determine G1 Mean: 8 weeks Baseline: BP, G1: Follow-up occurred (2006) efficacy of (olanzapine): 10±2.04mg/day CBC, weekly x 4weeks, then olanzapine for N = 6 chemistry ↓ Appetite: 1/6 biweekly x 4 weeks treatment of age: 6-14.8yrs Range: 7.5- profile, height, pervasive (mean: 12.5mg/day LFTs, pulse, ↑ Appetite: 3/6 Adverse effects developmental 9.25±2.9yrs) urinalysis, reported using the disorder vs M:F = 6:0 doses titration: weight Constipation: 3/6 “Olanzapine Side placebo <40kg: 2.5mg every Effect Checklist” G2 (placebo): other day for 3 days, Follow-up: EPS:0/6 N = 5 then 2.5mg daily adverse EPS monitored using age: 6.1-11yrs effects, BP, Glazed eyes: 1/6 the AIMS, Tardive (mean: >40kg: 2.5mg daily EPS, height, Dyskinesia Rating 8.9±2.1yrs) for 3 days, then 5mg pulse weight Headache: 1/6 Scale, and Barnes M:F = 3:2 daily Akathesia score Insomnia: 1/6 doses in both weight groups ↑ in 5mg Nervousness: 0/6 increments weekly Rhinitis: 1/6 max = 20mg/day Sedation: 4/6

Thirst: 0/6

Weight gain: 5/6

(mean: 3.4±2.2kg)

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

G2:

↓ Appetite: 0/6

↑ Appetite: 2/6

Constipation: 0/6

EPS:0/6

Glazed eyes: 0/6

Headache: 1/6

Insomnia: 0/6

Nervousness: 1/6

Rhinitis: 0/6

Sedation: 1/6

Thirst: 1/6

Weight gain: 1/6

(↑ of 0.7kg)

Shaw Compare G1 Mean: 8 weeks Baseline: G1: 1 pt receiving (2006) efficacy and (olanzapine): 18.1±4.3mg/day BMI, CBC, olanzapine withdrew safety of N = 13 ECG, EEG, ↓ ANC: 1/13 during week 2 (was olanzapine and Age: 6-17yrs Range: 5-20mg/day electrolytes, receiving 5mg daily) – clozapine in (mean: LFTs ↑ Appetite: 4/13 reason not specified children with 12.8±2.4yrs) dose titration: 5mg

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored childhood-onset M:F = 7:6 daily, ↑to 10mg on schizophrenia approx day 12, then Weekly: ↑ BMI: proportion of patients Adverse effects G2 (clozapine): ↑to 15mg at week 3 adverse not reported (mean: 1.4±1.6) reported using the N = 12 effects, CBC, Treatment Emergent Age: 6-17yrs Further ↑guided by EPS Constipation: 4/13 Symptom Scale Write- (mean: clinical judgment In 11.7±2.3yrs) Week 6: ECG, Difficulty Concentrating: M:F = 8:4 max = 20mg/day EEG, 1/13 EPS monitored using electrolytes, the AIMS, and LFTs ECG abnormalities: 1/13 Simpson Angus Scale

Study Enuresis: 1/13 Authors reported “few completion: EPS symptoms” BMI Hypersalivation: 4/13 experienced by patients in both groups. Hypertension: 1/11 There was no significant change in Insomnia: 1/13 AIMS or Simpson Angus scales from LFT abnormalities: 0/13 baseline over the course of the study. Somnolence: 2/13 All patients with ECG Tachycardia (>100bpm): 2/12 abnormalities were deemed fit to continue Weight gain: proportion of in the study by patients not reported cardiologist

(mean: 3.6±4kg)

G2:

↓ANC: 2/12

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

↑ Appetite: 4/12

↑ BMI: proportion of patients not reported (mean: 1.6±2.5)

Constipation: 2/12

Difficulty Concentrating: 4/12

ECG abnormalities: 2/12

Enuresis: 5/12

Hypercholesterolemia: 1/12

(mean cholesterol level: 6.8mmol/L)

Hypersalivation: 8/12

Hypertension: 7/11

Hypertriglyceridemia: 1/12

(mean triglyceride level: 5.3mmol/L)

Insomnia: 3/12

LFT abnormalities: 0/12

Somnolence: 3/12

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Tachycardia (>100bpm): 8/10

Weight gain: proportion of patients not reported

(mean: 3.8±6kg)

Prospective single-blind/open-label/naturalistic studies

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Wozniak Determine if co- G1 G1: 8 weeks Baseline: BP, G1: 4 patients from G1 (2009) administration of (olanzapine): Mean: BG, lipid withdrew – 2 withdrew topiramate with N = 17 8.6±3.4mg/day levels, Aches & Pains: 1/17 due to adverse effects olanzapine Age: 6-17yrs prolactin, and (1 patient ↑ appetite, 1 results in less (mean: G2: weight Agitation/activation: 2/17 patient tremor) weight gain and 10.2±2.6yrs) Mean: clinical M:F = 10:7 9.9±5.2mg/day Weekly: Anxiety: 1/17 Common improvement vs adverse spontaneously reported olanzapine G2 (olanzapine Range: 7.5- effects, BP, ↑ Appetite: 12/17 symptoms included monotherapy in + topiramate): 12.5mg/day weight increased appetite, children with N = 23 Cold/flu/allergies/infection: cold symptoms, bipolar disorder Age: 6-17yrs dose titration: 2.5mg Study 4/17 sedation, and headache (mean: daily, ↑ weekly as completion: 9.7±2.8yrs) tolerated by 2.5-5mg adverse Depression: 0/17 M:F = 11:12 effects, BG, max = 20mg/day BP, lipid Dry eyes, nose, or mouth: levels, 1/17

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored prolactin, and weight GI problems: 5/17

↑ BG: proportion of patients not reported (mean: 1.08mmol/L)

↑ HDL: proportion of patients not reported (mean: 0.14mmol/L)

Headache: 4/17

Neurological adverse effects (spacey, tremor, akathisia, dazed, nystagmus, speech deterioration): 3/17

↑ Pulse: proportion of patients not reported (mean: 10.8bpm)

↑ Prolactin: proportion of patients not reported (mean: 4.7ng/dL)

Sedation: 7/17

Sleep problems: 0/17

Skin Disturbance:1/17

Tics: 1/17

Urinary adverse effects: 0/17

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Weight gain: proportion of patients not reported (mean: 5.3±2.1kg)

G2:

Aches & Pains: 3/23

Agitation/activation: 3/23

Anxiety: 0/23

↑ Appetite: 10/23

↑ Cholesterol: proportion of patients not reported (mean: 0.63mmol/L)

Cold/flu/allergies/infection: 4/23

Depression: 1/23

Dry eyes, nose, or mouth: 0/23

GI problems: 3/23

↑ HDL: proportion of patients not reported (mean: 0.2mmol/L)

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Headache: 3/23

↑ LDL: proportion of patients not reported (mean: 0.31mmol/L)

Neurological adverse effects (spacey, tremor, akathisia, dazed, nystagmus, speech deterioration): 1/23

↑ Pulse: proportion of patients not reported (mean: 16.9bpm)

Sedation: 3/23

Sleep problems: 1/23

Skin Disturbance: 1/23

Tics: 0/23

↑ Triglycerides: proportion of patients not reported (mean: 0.76mmol/L)

Urinary adverse effects: 3/23

Weight gain: proportion of patients not reported (mean: 2.6±3.6kg)

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Fido Determine the N = 40 Mean: 7.5mg/day 13 weeks Baseline: BG, Drowsiness/sedation: 5/40 EPS monitored using (2008) efficacy and Age: 7-17yrs chest X-ray, the AIMS safety of (mean: Range: 5-10mg/day ECG, EPS, EPS: 4/40 olanzapine for 12.2±2.2yrs) hematology, No significant change the treatment of M:F = 40:0 dose titration: 2.5mg hepatitis B LFT abnormalities: 0/40 in AIMs score from children with twice daily for 1 serology, lipid baseline to week 13 autism week, dose then ↑(or profile, serum Weight gain: proportion of (all 4 patients with ↓) in increments of chemistry, patients not reported (mean: EPS had similar scores 2.5mg urinalysis, 0.25kg) at baseline) weight max = 10mg/day Drowsiness/sedation Study reported when completion treatment initiated but (13 weeks): not present by week 13 BG, chest X- ray, ECG, No significant changes EPS, in lab values measured hematology, hepatitis B serology, lipid profile, serum chemistry, urinalysis, weight

McCracken Determine the N = 12 Mean: 6 weeks Baseline: Drowsiness: 12/12 Adverse effects (2008) efficacy and Age: 7-14yrs 11.3±5.6mg/day ECG, spontaneously reported safety of (mean: hematology, ↑ Pulse: proportion of and monitored weekly olanzapine for 11.33±2.35yrs) Range: 2.5-20mg/day clinical patients not reported (mean: by physical the treatment of M:F = 11:1 chemistry, 13bpm) examination Tourette dose titration: urinalysis, Syndrome <40kg: 2.5mg every weight Weight gain: 12/12 (mean: Sedation and increased other day for 3 days, 4kg, range: 1.1-7.7kg) appetite frequently then 2.5mg daily for reported

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored 4 days, then 5mg daily for 1 week, Weekly: No clinically then ↑ in 5mg adverse effects significant changes increments as needed from baseline in lab Study values (all values >40kg: 2.5mg daily completion remained within for 3 days, then 5mg (week 6): normal limits for age) daily for 4 days, then adverse ↑ in 5mg increments effects, as needed hematology, clinical max = 20mg/day chemistry, urinalysis, weight

Quintana Evaluate the use N = 16 Mean (F): 9 weeks Baseline: BP, EPS: 3/16 EPS monitored using (2007) of olanzapine for Age: 8-17.9yrs 6.8±6.41mg/day CBC, the AIMS the treatment of (mean: chemistry Weight gain: proportion of children and 12.9±2.48yrs) Mean (M): profile, EPS, patients not reported (mean: 12/16 patients adolescents with M:F = 9:7 8.33±4.51mg/day HCG (if of completed all 10 schizophrenia childbearing 6.18±3.87kg) follow-up assessments Mean mg/kg dose: potential), – NO dropouts due to 0.17mg/kg pulse, adverse effects urinalysis, Range: 2.5-20mg weight Patients who experienced EPS dose titration: 2.5mg Weekly: received olanzapine daily, then ↑ (or ↓) in adverse 15-20mg/day increments of 2.5mg effects, BP, ever 4-8 days EPS, pulse, No clinically weight significant changes max = 20mg/day from baseline for BP, Study ECG, pulse, BG, or

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored completion: cholesterol/lipids when adverse evaluated effects, BP, retrospectively CBC, chemistry profile, EPS, HCG (if of childbearing potential), pulse, urinalysis, weight

Milin Evaluate the use N = 10 Mean = 8.25mg/day 12 weeks Baseline: ↑ BG: 0/10 Adverse Effects (2006) of olanzapine for Age: 10-15yrs ECG, monitored using a self- the treatment of (mean: Range = 5-15mg/day hematology, ECG abnormalities: 2/10 report “side effects children with 12.6±2.02yrs) physical exam (not thought to be from checklist” Asperger M:F = 10:0 dose titration: 2.5mg olanzapine) Disorder daily, then ↑ in Every 4 EPS monitored using increments of 2.5mg weeks: EPS: 0/10 the AIMs weekly hematology Weight gain: proportion of AIMs scored decreased max = 15mg/day BG, ECG, patients not reported (mean: from baseline – related EPS, height 4.69kg) to improvements in and weight stereotypic involuntary assessed at movements associated random with children with intervals Asperger Disorder

2 patients withdrew (12 patients enrolled, 10 evaluated) – exact reasons for dropout not reported

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Mean BMI within normal parameters at baseline and trial completion

Fatigue, loss of attentiveness, and nausea commonly reported

Mozes Compare G1 Mean: 12 weeks Baseline: BP, G1: 1 patient in olanzapine (2006) efficacy and (olanzapine): 8.18±4.41mg/day pulse, weight group lost to follow-up safety of N = 12 Akathisia: 3/12 olanzapine vs Age: 9-14yrs Range: 2.5-20mg/day Weekly: BP, EPS/akathisia risperidone for (mean: EPS, pulse, EPS: 7/12 monitored using the the treatment of 11.5±1.64yrs) dose titration: 2.5mg weight Barnes Akathisia childhood-onset M:F = 5:7 daily, then ↑ based Weight gain: proportion of Rating Scale and schizophrenia on clinical response Study patients not reported (mean: Simpson-Angus Scale G2 and adverse effects completion: 5.78±3.1kg) (risperidone): BP, EPS, N = 13 max = 20mg/day pulse, weight Age: 6-17yrs (mean: G2: 10.71±1.43yrs) M:F = 5:8 Akathisia: 1/13

EPS: 8/13

Weight gain: proportion of patients not reported (mean: 4.45±2.87kg)

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Sethi Evaluate the N = 6 Mean: 5.8mg/day 3-4months Not reported No adverse effects observed 1 patient received a (2006) efficacy of Age: 5-13yrs dose of 10mg daily olanzapine for (median: 9yrs) Range: 5-10mg/day (the remaining the treatment of M:F = 2:4 patients received 5mg Sydenham dose titration: daily) chorea 5mg daily, then ↑ based on clinical response after 1 week

max = 10mg/day

Biederman Evaluate G1 Mean: 8 weeks Baseline: BG, G1: Adverse effects (2005) olanzapine and (olanzapine): 6.3±2.3mg/day BP, lipid spontaneously reported risperidone for N = 15 levels, Aches & Pains: 1/15 the treatment of Age: 4-6yrs Range: 1.25- prolactin, 1 olanzapine patient bipolar disorder (mean: 10mg/day weight Agitation/activation: 1/15 withdrew due to in preschoolers 5±0.8yrs) adverse effects (↑ M:F = 10:5 dose titration: Weekly: Anxiety: 0/15 appetite and hand 1.25mg daily, then ↑ adverse tremor) G2 weekly as tolerated effects, BP, ↑ Appetite: 9/15 (risperidone): weight Common reported N = 16 max = 10mg/day Cardiovascular adverse adverse effects Age: 4-6yrs Study effects: 0/15 included ↑ appetite, (mean: 5.3±0.8y completion: cold/flu like yrs) adverse Cold/flu/allergies/infection: symptoms, sedation, M:F = 12:4 effects, BG, 6/15 and headache BP, lipid levels, Drooling: 0/15 prolactin, weight Dry eyes, nose, or mouth: 1/15

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

GI problems: 1/15

Headache: 2/15

Neurological adverse effects: 1/15

↑ Prolactin: proportion of patients not reported (mean: 11.9ng/dL)

↑ Pulse: proportion of patients not reported (mean: 17bpm)

Respiratory adverse effects: 0/15

Sedation: 3/15

Skin Disturbance:1/15

Urinary adverse effects: 2/15

Weight gain: proportion of patients not reported (mean: 3.2±0.7kg)

G2:

Aches & Pains: 0/16

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Agitation/activation: 2/16

Anxiety: 1/16

↑ Appetite: 8/16

↑ BP (systolic): proportion of patients not reported (mean: 9.8)

Cardiovascular adverse effects: 1/16

Cold/flu/allergies/infection: 5/16

Drooling: 1/16

Dry eyes, nose, or mouth: 3/16

GI problems: 4/16

Headache: 5/16

Neurological adverse effects: 0/16

↑ Prolactin: proportion of patients not reported (mean: 35.7ng/dL)

Respiratory adverse effects: 2/16

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Sedation: 4/16

Skin Disturbance:0/16

Urinary adverse effects: 1/16

Weight gain: proportion of patients not reported (mean: 2.2±0.4kg)

Stephens Evaluate the N = 10 Mean: 14.5mg/day 8 weeks Baseline: BP, Akathisia: 0/10 Adverse effects (2004) efficacy of Age: 7-13yrs clinical spontaneously olanzapine in (mean: Range: 1.25- chemistry, ↑ ALP: proportion of patients reported and actively reducing 9.9±1.7yrs) 20mg/day ECG, not reported (mean ↑ of 26.8) monitored using aggressive M:F = 9:1 hematology, adverse symptom behaviour in dose titration: 2.5mg height, pulse, Anxiety: 0/10 checklist children with daily for 2 weeks, weight Tourette then ↑ to 5mg daily ↑BP: 0/10 EPS monitored using Syndrome for 2 weeks (if Bi-weekly: the AIMS, and tolerated), then ↑in adverse Cognitive blunting: 0/10 Simpson Angus Scale 5mg increments bi- effects, BP, weekly as tolerated clinical Constipation: 0/10 ALP values remained chemistry, within normal limits max = 20mg/day ECG (at week Diarrhea: 0/10 for age 6 only), hematology, Dizziness: 0/10 Fatigue associated with height, pulse, dose ↑ and resolved for weight Dry mouth: 1/10 most patients over time

Study ECG abnormalities: 0/10 completion: adverse EPS: 0/10 effects, BP, clinical Fatigue: 4/10

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored chemistry, ECG, Headache: 5/10 hematology, height, pulse, Psychomotor slowing: 0/10 weight Weight gain: proportion of patients not reported (mean: 5.4±2.6kg)

Mozes Evaluate the N = 9 Mean: 10 weeks Baseline: BG, ECG abnormalities: 0/9 No scale used to (2003) efficacy of Age: 11-14yrs 15.56±4.64mg/day CBC, general measure EPS - olanzapine for (mean: serum EPS: 0/9 monitored by clinical the treatment of 12.5±1.13yrs) Range: 10-20mg/day chemistry, examination childhood-onset M:F = 10:0 ECG, EEG, ↑LFTs: 0/9 schizophrenia dose titration: 2.5mg kidney ECG and EEG resistant to daily for 4 days, then function tests, Somnolence: 7/9 repeated once during typical ↑ to 5mg daily for LFTs, physical olanzapine treatment antipsychotics approx. 2 weeks, exam, Weight gain: 9/9 (mean: then ↑in 5mg urinalysis 6.1±3.25kg) No adverse changes increments seen in blood Weekly: BP, chemistry, max = 20mg/day CBC, EPS, hematological, or EEG LFTs, weight parameters

Ross Evaluate the N = 19 Mean: Up to 1 All ↑BG: 0/10 Recruitment focused (2003) efficacy of Age: 6-15yrs 5.1±2.2mg/day at 3 year participants: on patients 12 and olanzapine for (mean: weeks, height, weight ↑BMI: 10/19 under (16/19 patients < the treatment of 10.5±2.4yrs) 6.1±3.6mg/day at 6 at each follow- 12yrs) childhood-onset M:F = 14:5 weeks, up visit EPS: 0/10 schizophrenia 7.7±4.1mg/day at 3 Follow-up occurred at months, Temperature change: 0/19 3 weeks, 6 weeks, 3 9.3±4.7mg/day at 6 months, 6 months, and months, Final 10 Weight gain: proportion of 1 year 10.4±3.5mg/day at 1 subjects to patients not reported (mean: year enroll: 1.6kg in 1st 3 weeks, 3.8kg 4 patients withdrew (2

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored over 6 weeks, 4.2kg over 3 after 6 weeks and 2 Baseline: BP, months, 9.7kg over 6 months, after 3 months) due to CBC, and 12.8kg over 1 year) weight gain chemistry panel, CPK, EPS monitored using EPS, LFTs, the AIMs, Barnes temperature Akathisia Scale, and Simpson Angus Scale 3 month follow-up: BP, No clinically CBC, significant changes chemistry from baseline to 3 panel, CPK, months in lab values EPS, LFTs, temperature

Kemner Evaluate the N = 25 Mean: 10.7mg/day 12 weeks Baseline: BP, Akathisia: 1/25 (3/25 with Adverse effects (2002) efficacy of Age: 6.4- clinical questionable akathisia) monitored via olanzapine for 16.6yrs (mean: Range: 2.5-20mg/day chemistry, observation and symptoms of 11.22yrs) ECG, ↑ Appetite: 14/25 questioning of patients pervasive M:F = not dose titration: electrolytes, developmental reported all patients: 2.5mg hematology, Asthenia: 14/25 EPS monitored using disorder daily or every other LFTs, physical the Barnes Akathisia day exam, pulse, ECG abnormalities: 4/25 Scale, and Simpson temperature, Angus Scale <55kg: ↑every other urinalysis, EPS: 3/25 week by 2.5mg/day weight 2 patients withdrew max = 15mg/day Nervousness: 6/25 (no explanation Bi-weekly: provided for 1 patient, >55kg: ↑every other adverse QTc prolongation: 0/25 parents unsatisfied week by 5mg/day effects, BP, with procedure for max = 20mg/day EPS, pulse, Salivation: 4/25 other patient) temperature, weight Somnolence: 6/25 EPS resolved in all 3 patients after dose

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored lowered ECG repeated Tremor: 5/25 3 times All lab tests within the Weight gain: 14/25 (mean ↑ normal range Lab tests of 5.8kg) repeated 1-2 times

Frazier Evaluate the N = 23 Mean: 8 weeks Baseline: Abdominal pain: 7/23 EPS monitored using (2001) efficacy and Age: 5.4- 9.6±4.3mg/day ECG, EPS, the AIMs, Barnes tolerability of 14.7yrs (mean: hematology, Akathisia: 2/23 Akathisia Scale, and olanzapine for 10.3±2.9yrs) Mean mg/kg dose: LFTs, physical Simpson Angus Scale the treatment of M:F = 13:10 0.21±0.1mg/kg/day exam, ↑ ALT (above normal limits): acute mania in prolactin, 2/23 1 patient withdrew at children and Range: 2.5-20mg/day urinalysis week 6 due to ↑ adolescents ↑ Appetite: 14/23 depressive symptoms dose titration: 2.5mg Weekly: BP, and suicidal ideation daily, then ↑ in EPS, height, BG abnormalities: 0/23 2.5mg increments pulse, weight 3 patients considered every 3 days ↑ BMI: 7/23 obese at trial (depending on Bi-weekly: completion based on patient response and Hematology, ↑ Cholesterol: 1/23 BMI (none at adverse effects) LFTs, beginning of the study) prolactin Depression: 6/23 max = 20mg/day (week 2 only) No clinical urinalysis Diarrhea: 5/23 signs/symptoms associated with Study EPS: 0/23 prolactin ↑ completion (week 8): BP, Fever: 5/23 No clinically ECG, height, significant changes in hematology, ↑ Heart rate: proportion of hematology parameters LFTs, physical patients not reported (mean: exam, 11.3±14.9bpm) prolactin,

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored pulse, urinalysis Infection: 5/23 weight ↑Prolactin (above normal limits): 6/21

↑ Pulse: proportion of patients not reported (mean: 9.8±14.5bpm)

Somnolence: 10/23

Weight gain: 7/23 (mean: 5±2.3kg)

Malone Obtain pilot data G1 Mean: 6 weeks Baseline: BP, G1: Adverse effects (2001) on safety, dosing (olanzapine): 7.9±2.5mg/day CBC, ECG, monitored using the and effectiveness N = 6 LFTs, height, Ataxia: 0/6 Dosage Record and of olanzapine Age: 4.9- Range: 5-10mg/day pulse, weight Treatment Emergent compared to 11.8yrs (mean: Behavioural toxicity: 0/6 Symptom Scale and haloperidol in 8.5±2.4yrs) doses titration: Weekly: Treatment Emergent children with M:F = 4:2 <40kg: 2.5mg every adverse Drowsiness: 5/6 Symptom Scale Write- autistic disorder other day effects, BP, In G2 weight Dry mouth: 1/6 (haloperidol): >40kg: 2.5mg daily EPS monitored using N = 6 Study Enuresis: 1/6 the AIMs, and Age: 4.9- doses in both weight completion: neurologic rating scale 11.8yrs (mean: groups ↑ in 2.5mg adverse EPS: 0/6 7.3±1.9yrs) increments up to effects, BP, No clinically M:F = 4:2 5mg/week CBC, ECG, Insomnia: 1/6 significant differences LFTs, height, in any lab values max = 20mg/day pulse, weight Nausea/vomiting: 2/6 measured

QTc prolongation: 0/6

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Rash: 0/6

Rigidity: 0/6

Tachycardia: 0/6

Weight gain: 6/6 (mean: 4.1±1.6kg, range: 2.7-7.1kg)

G2:

Ataxia: 1/6

Behavioural toxicity: 2/6

Drowsiness: 2/6

Dry mouth: 1/6

Enuresis: 1/6

EPS: 0/6

Insomnia: 0/6

Nausea/vomiting: 0/6

QTc prolongation: 0/6

Rash: 1/6

Rigidity: 1/6

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Tachycardia: 1/6

Weight gain: 5/6 (mean: 1.5±2.2kg, range: -2.5-4kg)

Weight loss: 1/6

Sholevar Report clinical N = 15 Mean: 4.8mg/day Mean: 11.3 Twice daily: Sedation: 11/15 No significant (2000) observations of Age: 6-13yrs days adverse autonomic or youth with (mean: Range: 2.5-5mg/day effects, BP, Weight gain: 0/15 hemodynamic adverse childhood-onset 9.4±1.99yrs) pulse, effects observed schizophrenia M:F = 9:6 dose titration: 1st 3 respiration, treated with patients: 5mg daily, and sedation olanzapine then ↓ to 2.5mg daily due to morning sedation and lethargy (1 patient remained on 2.5mg daily)

remaining 12 patients: 2.5mg daily for 5 days, then ↑ to 5mg daily

Retrospective Reviews

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored

Turkel Describe the N = 16 Mean: Mean: Not reported Cardiac arrhythmia: 0 /16 3/16 patients died of (2013) response to Age: 7-34mths 4.81±5.76mg/day 39±41.4 their underlying antipsychotic (mean: days EPS: 0/16 condition medication in 20.5±8mths) Range: 0.5-23mg/day

Author Study Aim Patient Olanzapine Dose Length of Adverse Adverse Effects Reported Comments Characteristics Treatment Effects Monitored infants and M:F = not toddlers reported dose titration: 0.125- Range: 2- experiencing 1.25mg qhs or bid, ↑ 151 days delirium based on efficacy

Turkel Describe the use N = 78 Mean: 10mg/day Mean: 26.5 Adverse Arrhythmia: 0/78 Dystonia resolved with (2012) of atypical Age: 1-18yrs days effects ↓ dose of olanzapine antipsychotics in (mean: Range: 0.625- obtained from Dystonia: 1/78 controlling 10.8±4.9yrs) 60mg/day Range: 1- patients’ 1 patient died due to symptoms of M:F = not 132 days) medical Metabolic syndrome: 0/78 their underlying delirium in reported records medical condition children and adolescents ADHD = Attention Deficit Hyperactivity Disorder; AIMs = Abnormal involuntary movement scale; ALP = alkaline phosphatase; ALT =alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BP = blood pressure; BG = blood glucose; BUN = blood urea nitrogen; CBC = complete blood count; ECG = electrocardiogram; EEG = electroencephalogram; EPS = extrapyramidal symptoms; GI = gastrointestinal; HR = heart rate; LFTs = liver function tests

Table 2.4 Synthesized adverse effects associated with olanzapine in young children*

Adverse Effect Number Number of Mean Percentage 95% Confidence of studies children with Adverse Interval evaluated Effect

Blood Glucose Abnormalities 3 43 4 1 to 17

54,58,62

Electrocardiogram Abnormalities 5 64 14 7 to 26

49,55,56,58,65

Extrapyramidal Symptoms 12 180 9 4 to 21

49,51,53-56,58-62,65

Liver Function Test Abnormalities 3 45 7 2 to 20

49,54,60

Sedation 12 191 48 35 to 67

49,51-54,56,57,60,64-66

Weight Gain 7 96 78 63 to 95

51,54-57,60,64

*Studies included for synthesis were prospective studies that reported adverse effects which were assessed objectively or which have been reported to be commonly observed in adolescents. Studies excluded from synthesis were retrospective reviews, case series, and case reports.

Table 2.5 Summary of adverse effects associated with olanzapine administration reported in all included prospective studies* and which were excluded from synthesis

Adverse Effect Number of Studies Evaluating Total Number of % Reported or Reporting Adverse Effect Patients Evaluated Incidence

Akathisia 4 70 9 (6/70)

54,55,59,65

Anxiety 3 42 2 (1/42)

52,65,66

Cold/flu-like symptoms 3 38 29 (11/38)

51,52,66

Constipation 3 29 24 (7/29)

49,51,65

Dry eyes/nose/mouth 4 48 8 (4/48)

52,56,65,66

Gastrointestinal problems 4 61 25 (15/61)

52,54,56,66

Headache 4 48 25 (12/48)

51,52,65,66

[17, 19, 25, 26]

Hypersalivation 3 53 15 (8/53)

49,52,55

Urinary adverse effects 4 51 8 (4/51)

49,52,56,66

*Cumulative reported incidence of adverse effects that were not included in the meta-analysis but that were evaluated in at least 3 prospective studies. These adverse effects were not synthesized in the meta-analysis because they are either not measured objectively or have not been reported to be commonly observed in adolescents.

Table 2.6 Summary of Case Reports

Author Patient Characteristics Olanzapine Dose Length of Adverse Adverse Effects Comments Treatment Effects Reported Monitored

Taskiran (2013) N = 1 Titrated to 15mg 2 months Not reported No sedation Age: 7.5yrs daily Sex: M Diagnosis: pervasive developmental disorder

Bozkurt (2010) N = 1 5mg daily Not reported Not reported Catatonia Olanzapine unlikely cause Age: 11yrs of catatonia based on Sex: M No dystonia, tremor, patient presentation Diagnosis: catatonia tardive dyskinesia or fever

Herguner (2010) N = 1 2.5mg daily, ↑ to Not reported Not reported Excessive masturbation Complete resolution of Age: 6yrs 7.5mg daily masturbatory behaviour Sex: M after discontinuation of Diagnosis: autistic disorder olanzapine

Ferreira Maia N = 1 15mg daily Not reported Not reported No significant weight gain (2007) Age: 10yrs Sex: M Diagnosis: bipolar disorder

Emiroglu (2006) N = 1 15mg daily 6 months Not reported Did not experience any Age: 8yrs adverse effects Sex: F Diagnosis: bipolar disorder

Beresford (2005) N = 1 8.75mg daily, ↓ Not reported Not reported ↑ Appetite Dose ↓ due to significant Age: 4.25yrs to 3.75mg daily weight gain over 1 month Sex: M after 1 month Weight gain: 6.8kg Diagnosis: schizophreniform disorder

Author Patient Characteristics Olanzapine Dose Length of Adverse Adverse Effects Comments Treatment Effects Reported Monitored

Chungh (2005) N = 1 2.5mg daily 2 days Not reported Neuroleptic malignant Temperature ↓ to 36.5°C Age: 12yrs syndrome (↑ CPK, LDH, when olanzapine stopped Sex: F elevated temperature) Diagnosis: Olanzapine 2.5mg re- Bipolar disorder and mild started – symptoms of mental retardation olanzapine-induced neuroleptic malignant syndrome returned

Courvoisie(2004) N = 1 2.5mg QHS Approx. 9 Not reported ↑ BG: 14.4mmol/L Detection of ketones in Age: 7yrs months the urine may have been a Sex: M Urine positive for glucose false positive secondary to Diagnosis: and ketones use of valproic acid ADHD, bipolar disorder, and oppositional defiant Weight gain: 7.8kg (over disorder 1 year)

Ercan (2004) N = 1 5-15mg/day Not reported ECG, EPS, EPS: no change in ESRS EPS monitored using the Age: 12yrs LFTs, and score Extrapyramidal Symptom Sex: M weight Rating Scale (ESRS) Diagnosis: schizophrenia Mild sedation Pt followed for 26 weeks Weight gain: 6kg (over 26 (exact treatment duration weeks) not reported)

No clinically significant changes in ECG or LFTs

Boachie (2003) N = 4 2.5mg daily Not reported Not reported Weight gain: 4/4 Weight gain was goal Age: 10-12yrs (mean: 11yrs) (≈1-1.2kg per week) No adverse effects M:F = 1:3 reported Diagnosis: anorexia nervosa

Author Patient Characteristics Olanzapine Dose Length of Adverse Adverse Effects Comments Treatment Effects Reported Monitored

Sheikh (2002) N = 1 Range: 2.5- 15 days Not reported ↑ Appetite Age: 10yrs 7.5mg/day Sex: F Weight gain: 3.2kg (over Diagnosis: acute agitation Max total daily 15 days) and history of ADHD dose = 10mg

Mehler (2001) N = 1 5mg daily Not reported Not reported Weight gain: 4.6kg (over Weight gain was goal Age: 12yrs 7 weeks) Sex: F No adverse effects Diagnosis: anorexia reported nervosa

Nguyen (2001) N = 1 5mg daily Several months Not reported ↑ Total cholesterol: Five weeks after stopping Age: 10yrs (specific time 5mmol/L olanzapine: Sex: M frame not Diagnosis: ADHD reported) ↑ Triglycerides: - patient lost 9kg 2.06mmol/L - total cholesterol: Weight gain: 9kg (over 3.9mmol/L (151mg/dL), - several months) triglycerides: 0.7mmol/L (61mg/dL)

Bengi Semerci N = 1 5mg daily, ↑ to Not reported Not reported ↑ Appetite (2000) Age: 9yrs 10mg daily Sex: M Diagnosis: Tourette’s disorder

Chang (2000) N = 3 Range: 2.5-5mg 1-3months Not reported Sedation: 2/3 Sedation resolved after 3 Age: 9-12yrs (mean: daily days in 1 patient, mild 10.3yrs) Weight gain: 2/3 (Range: daytime sedation persisted Sex: M 4.5-8kg) in other patient. Diagnosis: acute mania Olanzapine stopped in 1 patient due to weight gain.

Author Patient Characteristics Olanzapine Dose Length of Adverse Adverse Effects Comments Treatment Effects Reported Monitored

Lavid (1999) N = 2 Range: 1.25- 2-5mths Not reported Sedation: 0/2 No adverse effects Age: 9-10yrs (mean: 2.5mg daily reported for either pt 9.5yrs) Weight gain: 0/2 Sex: M Diagnosis: stuttering

Krishnamoorthy N = 5 Mean: 7.5mg/day 14-52 days Not reported Akathisia: 2/5 (1998) Age: 6-11yrs (mean: 9.2yrs) Mean mg/kg Sedation: 2/5 M:F = 2:3 dose: Diagnosis: psychiatric 0.22mg/kg/day Weight gain: 3/5 (↑ of 4- disorder 8kg) Range: 2.5- 10mg/day

Malek-Ahmadi N = 1 5-7.5mg daily Not reported Not reported No adverse effects (1998) Age: 8yrs reported Sex: M Diagnosis: hyperactivity and aggressive behaviour N = 2 Horrigan (1997) Age: 9-10yrs (mean: Range: 5-20mg Not reported Not reported EPS: 0/2 9.5yrs) daily Sex: M Mild sedation: 1/2patients Diagnosis: mental retardation, bipolar No other adverse effects disorder, and autistic reported for either patient behaviour ADHD = Attention Deficit Hyperactivity Disorder; CPK = creatinine phosphokinase; ECG = electrocardiogram; EPS = extrapyramidal symptoms; LDH = lactate dehydrogenase; LFTs = liver function tests

Table 2.7 Summary of Overdose/Toxic Dose Articles

Author Patient Olanzapine Olanzapine Other Medications Clinical Onset and Abnormal Treatment/ (Year) Characteristics Dose Level Ingested Presentation Duration Laboratory of Values Follow-Up Adverse Effects (normal reference range)*

Hail (2013) age: 6yrs 75-100mg Not reported Sertraline, Tachycardia, Onset: 1 hr K: 2.9mmol/L Supportive (2.5-3.3mg/kg) topiramate, combative, (3.7-5mmol/L) care, sex: M melatonin and drowsy, Duration: lorazepam, guanfacine agitation, 48-96 hrs diphen- weight: 30kg (olanzapine the only delirium hydramine, medication taken at physostigmine, a higher dose than dexmed- that prescribed) etomidine, diazepam

Tanoshima age: 17mths 20-50mg 137ng/mL None Lethargy, Onset: Lab values Activated (2013) (1.6-3.9mg/kg) (24 hrs post- drowsiness, unknown reported as charcoal, sex: F ingestion) EPS (ataxia (within 3.5 within normal intubation, and tremor) hrs post- limits by supportive care weight: 12.8kg and fever 24 ingestion authors hrs post- ingestion Duration: Fever continued Prolactin: for 3 days, 16.7mcg/L (on ataxia and day 2) and tremor 13.3mcg/L (on continued day 3) for 5 days (3-15mcg/L)

Lankheet age: 28mths Reported: 30mg 888ng/mL None Loss of Onset: 6 Lab values Supportive (2011) (2.3mg/kg) (approximately consciousness, hrs reported as care (oxygen, sex: F 6 hrs post- slurred speech, within normal normal saline Estimated ingestion agitation, Duration: limits by bolus), full weight: 13kg based on levels: tachycardia, 36 hrs authors recovery 115-230mg 197ng/mL hypertension within 36 hrs (8.8- (30 hrs post- then 17.7mg/kg) ingestion) hypotension

106ng/mL (42 hrs post- ingestion

Kochhar age: 12yrs 210mg 430ng/mL Possibly paroxetine Agitation, Onset: Lab values Charcoal, (2002) (approximately and combative, approximat reported as supportive sex: M 1 hr post- dextroamphetamine/ miosis, ely 1 hr within normal care, no long- ingestion) amphetamine somnolence, post- limits by term weight: not ingestion authors complications reported 100ng/mL reported at 3 (3 days post- Duration: month follow- ingestion) 36 hrs up

Bond age: 6yrs 10mg Not reported Possibly albuterol Slurred Onset: Not reported None (1999) (0.6mg/kg) speech, Could not sex: F staggering be aroused [61] gait, extreme 15 hrs weight: 17kg drowsiness, post- pruritic rash, ingestion lethargy, ataxia, tremor Duration:

Bonin age: 12mths Unknown 340ng/mL Possibly Lethargy, Onset: 1 hr All reported Activated (1999) (approximately benztropine “bicycling lab values charcoal, sex: M 5 hrs post- (undetected in urine movements of Duration: within normal admitted to ingestion) and serum drug limbs”, 15-16 hrs limits Pediatric weight: 11kg screen) irritability, Intensive Care agitation, Unit for initial monitoring, tachycardia discharged the following day without complication

Catalano age: 18mths 30-40mg 213ng/mL None Somnolence, Onset: not K: 3.5mmol/L Initially given (1999) (2.7-3.6mg/kg) (4 hrs post- combative, reported (3.7-5mmol/L) 2 tsp syrup of sex: M ingestion) tachycardia, ipecac, decreased Duration: BUN: activated weight: 11kg respiratory clinical 8.2mmol/L charcoal, rate improveme (2.9- gastric lavage, nt 4 hrs 7.1mmol/L) intubated, post- discharged the ingestion, BG: following day vital signs 7.5mmol/L in stable

Chambers age: 9yrs 100mg Not reported Acetaminophen Combative, Onset: 2 AST: 93 (≤45) Activated (1998) (3.4mg/kg) (unknown amount) tachycardia, hrs (EPS charcoal, N- sex: M hypotension, developed ALT: 47 (≤40) acetyl cysteine, decreased 36 hrs norepinephrine weight: 29kg gastrointestina post- , cisapride + l motility, EPS ingestion) ondansetron + metoclopramid Duration: e (for 36 hrs – 13 promotility days effects), (presenting diphenhydrami symptoms ne (for EPS) resolved within 36 hrs and EPS continued for 13 days)

Yip (1998) age: 2.5yrs 7.5-15mg 11ng/mL None Somnolence, Onset: 1 hr Lab values Monitored and (0.6-1.1mg/kg) (10 hrs post- agitation, reported as improved to sex: M ingestion) irritability, Duration: within normal normal within hostility, 24 hrs limits by 24 hrs weight: 13.5kg authors tachycardia,

*Normal reference ranges based on age and gender specific reference range used by The Department of Pediatric Laboratory Medicine at the Hospital for Sick Children ALT =alanine aminotransferase; AST = aspartate aminotransferase; BG = blood glucose; BUN = blood urea nitrogen; EPS = extrapyramidal symptoms; K = potassium

Chapters 3: Olanzapine for Treatment and Prevention of Acute Chemotherapy-induced Vomiting in Children: A Retrospective, Multi-center Review

The contents of this chapter have been published in Pediatric Blood and Cancer and are included in this thesis with permission of Wiley Periodicals, Inc. : Flank J, Thackray J, Nielson D, August A, Schechter T, Alexander S, Sung L, Dupuis LL. Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review. Pediatric Blood and Cancer. 2015 March; 62(3): 496-501. E-pub October 2014. Copyright 2014 by Wiley Periodicals, Inc.

In addition to acting as the primary author of this manuscript, I assisted with data collection and review of patient charts of those patients included from The Hospital for Sick Children, including completion of data collection forms. Data collection for external sites was completed by the designated co-author at each particular site (J. Thackray – Memorial Sloan Kettering Cancer Center, D. Nielson – Children’s Medical Center, A. August – Children’s Mercy Hospitals and Clinics). I developed the data collection form for use at participating sites. I was responsible for communicating with the co-authors at the centers involved to ensure consistent methods were used for data collection by individuals at participating sites. I also entered the data from all sites into the study database and assisted with summarizing and analyzing the data.

3.1 Abstract

Background: This retrospective review provides preliminary data regarding the safety and efficacy of olanzapine for chemotherapy-induced vomiting (CIV) control in children. Methods: Children<18 years old who received olanzapine for acute chemotherapy-induced nausea and vomiting (CINV) control from December 2010 to August 2013 at four institutions were identified. Patient characteristics, chemotherapy, antiemetic prophylaxis, olanzapine dosing, CIV control, liver function test results and adverse events were abstracted from the health record. Toxicity was graded using CTCAEv4.03. Results: Sixty children (median age 13.2 years; range: 3.10–17.96) received olanzapine during 158 chemotherapy blocks. Olanzapine was most often (59%) initiated due to a history of poorly controlled CINV. The mean initial olanzapine dose was 0.1 mg/kg/dose (range: 0.026–0.256). Most children who received olanzapine beginning on the first day of the chemotherapy block experienced complete CIV control throughout the acute phase (83/128; 65%). There was no association between the olanzapine dose/kg and complete CIV control (OR 1.01; 95% CI: 0.999– 1.020; P=0.091). Sedation was reported in 7% of chemotherapy blocks and was significantly associated with increasing olanzapine dose (OR: 1.17; 95% CI: 1.08–1.27; P=0.0001). Of the 25 chemotherapy blocks where ALT and/or AST were reported more than once, grade 1–3 elevations were observed in five. The mean weight change in 31 children who received olanzapine during more than one chemotherapy block was 0% (range: -22 to +18). Conclusion: Olanzapine may be an important option to improve CIV control in children. Prospective controlled evaluation of olanzapine for CINV prophylaxis in children is warranted.

3.2 Introduction

Olanzapine is an atypical antipsychotic agent with demonstrated efficacy in controlling chemotherapy-induced nausea and vomiting (CINV) in adult oncology patients.28-30,34-36,100 For example, in a randomized controlled trial in chemotherapy-naive adult oncology patients receiving highly emetogenic chemotherapy, olanzapine provided comparable control of chemotherapy-induced vomiting (CIV) to aprepitant (complete control: 100% vs. 87% for acute phase, 75% vs. 70% for delayed phase).30 Compared to aprepitant, olanzapine has the added

70 advantages of a reduced potential to interact with other antiemetic or antineoplastic agents and being less expensive. Currently, olanzapine is recommended for the treatment of CINV despite guideline-consistent prophylaxis or breakthrough CINV in adult oncology patients.18,38

Olanzapine is approved for the treatment of schizophrenia and bipolar disorder in adolescents in the United States and has a track record of safe use in younger children with psychiatric illness.43,45,62 When taking olanzapine for chronic illness, adults may experience adverse effects such as weight gain, sedation, extrapyramidal symptoms (EPS), abnormalities in liver function tests (LFTs) and increased blood glucose, prolactin, cholesterol and/or triglycerides concentrations.19 Adolescents receiving olanzapine may be at increased risk of experiencing some of these adverse effects including weight gain, increased body mass index, and elevated blood glucose, cholesterol, triglyceride, and prolactin concentrations.46-48 However, adult oncology patients taking olanzapine for short periods of time for CINV prophylaxis have reported few adverse effects and, when they have occurred, adverse effects have been minor and reversible (e.g., sleepiness).30,32 The positive experience with olanzapine reported in adult oncology patients has prompted some pediatric clinicians to prescribe olanzapine for individual children receiving chemotherapy. However, there are no published descriptions of its use for CINV control in children. We undertook this multicenter, retrospective study to explore the efficacy and safety of olanzapine in children when given for CINV control.

3.3 Methods

This study was approved by the Research Ethics Boards of all institutions; the requirement for informed consent was waived. Children less than 18 years of age who received olanzapine at participating centers (Children’s Medical Center, Dallas, USA; Memorial Sloan Kettering Cancer Center, New York, USA; Children’s Mercy Hospitals and Clinics, Kansas City, USA; The Hospital for Sick Children, Toronto, Canada) from December 1, 2010 to August 1, 2013 were identified from pharmacy dispensing records. Children who received oral olanzapine for the purpose of CINV control and who received olanzapine during the acute phase of a chemotherapy block were eligible for inclusion in this review. Children who had been receiving olanzapine for a condition unrelated to CINV control before chemotherapy administration or

71 who began to receive olanzapine during a chemotherapy block for a condition unrelated to CINV control were excluded. The following data were abstracted from each child’s health record (including but not restricted to the daily progress notes, nursing flow sheets, medication administration records, and medication reconciliation forms): age, weight, height, and sex; diagnosis and date of diagnosis; antineoplastic and antiemetic agents received; reason for olanzapine use; olanzapine dose and duration; reason for olanzapine discontinuation; number of vomits on each day during chemotherapy; liver function test results (plasma aspartate aminotransferase [AST], alanine aminotransferase [ALT], and bilirubin concentrations) during olanzapine therapy; reports of drowsiness or dizziness during olanzapine therapy; and any adverse effect noted in the chart to be attributed to olanzapine.

The emetogenicity of the antineoplastic agents administered was assessed according to the guideline of the Pediatric Oncology Group of Ontario.9 A chemotherapy block was defined as a series of consecutive days that chemotherapy was administered. The acute phase was defined as the period starting with the first chemotherapy dose of the block and continuing for 24 hours after administration of the last chemotherapy dose of the block. In patients receiving 24-hour methotrexate infusions, the acute phase was defined as beginning with the start of the methotrexate infusion and ending 24 hours after completion of the methotrexate infusion.

The primary outcome measure was the number of times a child vomited each day of the acute phase. CIV was deemed to be completely controlled if no vomits or retches were recorded in the health record during the entire acute phase. CIV was judged to be partially controlled if no more than two vomits or retches occurred on any day during the acute phase while CIV was defined as uncontrolled if more than two vomits or retches were recorded on any day during the acute phase.11 In patients who received olanzapine for the treatment of breakthrough CIV, CIV control on the day following olanzapine was determined. Nausea severity was not recorded since it was not routinely assessed in all patients and, when it was assessed, the assessment method was not standardized or validated. Severity of sedation and elevation in plasma ALT or AST concentration was graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.101 The likelihood that sedation or elevation in plasma ALT or AST concentration was caused by olanzapine was assessed by the method of Naranjo et al.102

The data were described using means, ranges, and standard deviation. The relationship between CIV control and olanzapine dose (in mg/kg/dose) and patient age as well as sedation were examined using logistic regression with generalized estimating equations (GEE) to account for each child potentially contributing more than one episode. The magnitude of the association was described using the odds ratio (OR) and the 95% confidence interval (CI) (SAS Enterprise Guide version 4.3).

3.4 Results

Sixty children received olanzapine for the purposes of CINV prophylaxis or treatment over 158 chemotherapy blocks during the study period. Four chemotherapy blocks were given as hematopoietic stem cell transplant conditioning. Thirty-one children received olanzapine during more than one chemotherapy block. Demographic data are presented in Table 3.1. The chemotherapy blocks during which olanzapine was administered are described in Table 3.2.

Characteristics of olanzapine use for CINV control are presented in Table 3.3. Olanzapine was most often initiated either as an immediate response to uncontrolled CINV in the current chemotherapy block (27/158; 17%) or to prevent CINV in a child with a history of poorly controlled CINV in a past chemotherapy block (94/158; 59%). Olanzapine was given as either the standard oral tablet or the oral dissolving tablet. Doses were rounded to the nearest 1.25 mg or 2.5 mg depending on the sizes of olanzapine tablets available at each institution and each institution’s policies with respect to tablet-splitting. The mean initial single olanzapine dose administered was 0.10±0.051 mg/kg/dose. The maximum single dose administered was 10 mg.

CIV control was evaluated in the 128 chemotherapy blocks where olanzapine was started on the first day of chemotherapy. Most of these contained highly emetogenic therapy (106/128; 83%). In addition to olanzapine, patients received ondansetron or granisetron (125/128; 98%), dexamethasone (71/128; 55%), and/or aprepitant (22/128; 17%) on a scheduled basis. Specifically, the following combinations of antiemetic agents were given on a scheduled basis: ondansetron or granisetron alone (33/128; 26%); ondansetron or granisetron plus dexamethasone (41/128; 32%); ondansetron or granisetron plus dexamethasone plus aprepitant (10/128; 8%); ondansetron or granisetron plus aprepitant (6/128; 5%); or ondansetron or granisetron plus

73 dexamethasone plus lorazepam (6/128; 5%). In 83 (65%) of these chemotherapy blocks, CIV was completely controlled and no vomiting or retching was reported at any time during the acute phase. In order to assess the impact of the addition of olanzapine to guideline-consistent CINV prophylaxis, CIV control was assessed in patients with a history of CINV prophylaxis failure receiving ondansetron or granisetron with or without dexamethasone during highly emetogenic chemotherapy blocks. In 23 of these 35 chemotherapy blocks, CIV was completely controlled (66%). Among the chemotherapy blocks where olanzapine was initiated on the first day of chemotherapy, there was no association between the olanzapine dose/kg and complete CIV control (OR 1.01; 95% CI: 0.999–1.020; P=0.091). This also held true when CIV control was evaluated only in highly emetogenic chemotherapy blocks (OR 0.99; 95% CI: 0.87–1.13; P=0.873). Among the highly emetogenic chemotherapy blocks where olanzapine was initiated on the first day of chemotherapy, there was no association between patient age and complete CIV control (OR 1.02; 95% CI: 0.913–1.140; P=0.725).

CIV control on the day following olanzapine administration was assessed in 21 chemotherapy blocks in 20 children who received olanzapine for the treatment of breakthrough CINV. Complete CIV control was reported the day following the first olanzapine dose in 12 chemotherapy blocks (57%) while partial and failed CIV control were reported in 29% and 14%, respectively.

The most commonly reported adverse events during olanzapine administration were: sedation (11/158; 7%) and increased plasma transaminase concentrations (5/25; 20%). Grade 1 (seven cases) and 2 (four cases) sedation was reported in 10 patients during 11 chemotherapy blocks. Other sedating antiemetic agents were given concurrently with olanzapine in nine of the 11 chemotherapy blocks associated with any sedation: lorazepam (8/11), hydroxyzine (3/11), diphenhydramine/dimenhydrinate (3/11), and/or nabilone (1/11). As assessed by the Naranjo method [21], 10 episodes of sedation were possibly associated with olanzapine while one was probably associated with olanzapine. Sedation was transient and no specific action was taken to manage it in six (55%) cases. In four cases the olanzapine dose was reduced. Olanzapine was discontinued due to grade 2 sedation in one patient with a cerebrospinal fluid leak following a lumbar puncture. This was the only instance where an adverse effect prompted the discontinuation of olanzapine. Five patients went on to receive olanzapine during subsequent chemotherapy blocks. Two of these patients received three and four subsequent chemotherapy

74 blocks, respectively, accompanied by the same olanzapine dose; no sedation was reported in either patient. Another two patients received olanzapine during subsequent chemotherapy blocks at half doses without sedation while another patient received the same dose of olanzapine during seven chemotherapy blocks with sedation being reported only in two. The mean initial olanzapine dose given to children who did and did not experience sedation was 0.14 ± 0.033mg/kg/dose (range: 0.093–0.20 mg/kg/dose) and 0.09 ± 0.051 mg/kg/dose (range: 0.03– 0.26 mg/kg/dose). Sedation was significantly associated with increasing olanzapine dose (OR: 1.17; 95% CI: 1.08–1.27; P=0.0001).

Change in liver function test results were evaluated in the 25 chemotherapy blocks where liver function tests were reported on the first day of the chemotherapy block and at least once again during the period of olanzapine administration. Five patients experienced elevations in AST (Grade 1: 1/5; Grade 2: 3/5) and/or ALT (Grade 1: 1/5; Grade 2: 3/5; Grade 3: 1/5) during five chemotherapy blocks. As assessed by the Naranjo method [21], liver function test elevations were possibly or probably related to olanzapine administration in four and one cases, respectively. Plasma AST and ALT concentrations ranged from 1.1 to 5 and 2.6 to 7.1 times the upper limit of normal for age, respectively. In the child who experienced Grade 3 elevation in plasma ALT concentration, the plasma ALT concentration decreased during the olanzapine course and was 1.6 times the upper limit of normal 4 days after the maximum elevation. Bilirubin was unaffected in all patients. These patients were receiving the following chemotherapy concurrently: high dose methotrexate (2), ifosfamide plus etoposide (2), and cyclophosphamide (1). Two patients, including the patient who experienced grade 3 elevation in plasma ALT concentration, went on to receive olanzapine during subsequent chemotherapy blocks. Liver function results were available twice during the acute phase during only one chemotherapy block for one of these patients. Results remained less than 3 times the upper limit of normal for age for this patient.

To limit the influence of normal growth on the assessment of olanzapine-associated weight gain, body weight at the start of the first chemotherapy block was compared to that at the start of the next chemotherapy block in 26 patients (82 chemotherapy blocks) who received olanzapine during more than one chemotherapy block within the study period which were no more than 6 weeks apart. The mean change in body weight from the first to the next chemotherapy block where olanzapine was administered was 0% (range: -22 to 18%). Patients lost weight in between

36 consecutive chemotherapy blocks and experienced no weight change in between nine chemotherapy blocks. Three patients experienced a weight increase of more than 10% in between three consecutive chemotherapy blocks where olanzapine was administered.

Details regarding the use of olanzapine for CINV control in children receiving chemotherapy including other adverse events reported during olanzapine administration are presented in Table 3.4.

3.5 Discussion

We have described the efficacy and safety of olanzapine for CIV control in 60 children receiving 158 chemotherapy blocks in four institutions in two countries. When olanzapine was given together with standard antiemetic agents from the beginning of the chemotherapy block, 65% of children achieved complete CIV control. In addition, the adverse events reported with its use were transient and of minor clinical significance.

Most children in this study were offered olanzapine after having experienced poor CINV control in previous chemotherapy blocks despite standard antiemetic prophylaxis. In adults, failure of CINV control is a known risk factor for poor CINV control in the future. In a recent study, adult patients who experienced CINV during the first administration of highly emetogenic chemotherapy were 3.7 times more likely (95% CI: 2.88–4.74; P<0.0001) to experience CINV with subsequent cycles than were patients who had not experienced CINV.103 While pediatric- specific data about the impact of previous failure of CINV control is not available, it is likely that CINV would have been particularly difficult to control in the children included in this study. It is remarkable then that when olanzapine was administered from the beginning of the chemotherapy block, most children achieved complete CIV control. Most children who received olanzapine for the treatment of breakthrough CIV also achieved complete CIV control on the day following the first dose. Our observations suggest that olanzapine may be an important option to prevent or treat CIV in children.

Olanzapine dosing was at the discretion of each prescriber. It is not possible to determine the method of dose selection used. Doses used in studies of olanzapine in children less than 13 years

76 of age with psychiatric conditions or behavioural disorders have ranged from 0.5 to 60 mg/day; this, together with the olanzapine dose recommended for adult oncology patients (10 mg daily) may have been used as a guide by some prescribers.104 In the absence of pharmacokinetic and pharmacodynamic pediatric dose-finding studies, scaling methods have been proposed for the conversion of adult doses to effective and safe doses for use in infants and children.105 Such methods may have been used by some prescribers to derive pediatric olanzapine doses for CINV control. Olanzapine doses derived using this technique range from 0.14 mg/kg/dose in children weighing 70 kg to 0.2 mg/kg in children weighing 15 kg. As would be expected with a drug such as olanzapine which is metabolized primarily by CYP1A2, children aged 2–10 years may require a higher dose on a mg/kg basis than older children and adolescents.106

We did not observe a significant relationship between the probability of complete CIV control and olanzapine dose. This may have been due to the relatively small sample size evaluated, the widely varying olanzapine doses administered and the possibility that dose selection may have been biased by patient-related factors such as severity of CINV. However, decisions regarding initial olanzapine dosing in children for the purpose of CINV control should also be based on possible dose-related toxicity.

Sedation, elevations in plasma AST and ALT concentrations, and weight gain have been more commonly reported in adolescents receiving chronic olanzapine therapy than in adults.19 A systematic review and meta-analysis of published reports of the use of olanzapine in children less than 13 years of age observed that of the 254 children participating in 17 prospective studies evaluating olanzapine for the treatment of psychiatric conditions or behavioural disorders, weight gain or sedation were reported in 78% (95% CI: 63–95%) and 48% (95% CI: 35–67%), respectively.104 Electrocardiogram abnormalities or extrapyramidal symptoms were reported in 14% (95% CI: 7–26%) and 9% (95% CI: 4–21%), respectively, while elevation in liver function tests or blood glucose abnormalities were reported in 7% (95% CI: 2–20%) and 4% (95% CI: 1– 17%), respectively. No deaths were attributed to olanzapine including after olanzapine poisoning. These results should be considered when evaluating the risks and benefits of olanzapine for individual patients but must be interpreted in light of the prolonged duration of olanzapine administration in these studies.

Similar to the results of the meta-analysis and in reports of olanzapine use in adult cancer patients, sedation was the most commonly noted adverse effect associated with olanzapine use in our study. Our patients received olanzapine for short periods of time and adverse events were reported in few chemotherapy blocks. All patients received olanzapine at a dose far lower than the dose which has been proposed to be the dose threshold to produce clinical symptoms after olanzapine poisoning (0.4 mg/kg/dose).99 The relatively low incidence of adverse effects reported in our cohort and the concurrent administration of other medications known to cause similar adverse events such as antiemetic agents and chemotherapy confound the ability to determine the strength of the relationship between these adverse events and olanzapine administration. The reported adverse events were transient and of minor clinical significance. Children who experienced an adverse event during one chemotherapy block often went on to receive olanzapine at the same dose during a subsequent chemotherapy block without any adverse event being reported. Nevertheless, based on our preliminary observations on the relationship between sedation and olanzapine dose, it would be prudent to administer olanzapine in doses at or below the lower end of the dose range derived by allometric scaling in future studies in children receiving chemotherapy.

Olanzapine is approved in the United States for administration to adolescents 13 years of age and older with psychiatric conditions. In Canada, olanzapine is approved for use in adults only. The off-label use of drugs in children has been identified as a common practice in the United States, Canada, and other jurisdictions.107-110 Pediatric clinicians may use drugs off-label in situations where the usual standard of care is perceived to be inadequate and a drug has demonstrated efficacy and safety in adult patients. However, off-label drug use may expose children to ineffective or unsafe treatment since the doses used ad hoc are not adequately studied. We do not suggest olanzapine be adopted as a standard approach for CINV prophylaxis in children at present. Prospective, controlled trials must first be conducted to determine its efficacy and safety. We suggest that an initial once daily olanzapine dose of 0.1 mg/kg/dose (maximum: 10 mg/dose) be evaluated in such trials. This dose is lower than that suggested by allometric scaling and could be increased to 0.14 mg/kg/dose (max: 10 mg/dose) if CIV is not controlled and sedation does not occur or is not troublesome.

This study is limited by its retrospective design. Data were limited to the information available in the health record. Information regarding nausea severity was not able to be collected since health

78 care providers did not chart nausea severity routinely or uniformly. When nausea was mentioned in the medical record, a validated pediatric nausea assessment tool was not used to determine its severity. Similarly, information regarding the incidence of retching was limited since nurses did not routinely chart its presence or absence. In cases where the patient was discharged before 24 hours had elapsed following administration of the last chemotherapy dose of the block, complete data were not available for the last 24 hours of the acute phase. Since the antiemetic prophylaxis provided was not standardized, it is not possible to determine the true contribution of olanzapine to CIV control. In addition, the lack of information regarding the antiemetic agents provided in chemotherapy blocks prior to those evaluated in this study limits our confidence that patients who were identified as having a history of failed antiemetic prophylaxis had refractory CINV. Finally, the number of olanzapine courses during which inducers or inhibitors of CYP 1A2 were administered and the impact this may have had on olanzapine activity is unknown. The assessment of potential adverse events associated with olanzapine administration was limited to those identified and documented by the health care providers caring for each patient. Mild to minor adverse events may have been missed as a result. However, it is doubtful that serious adverse events such as extrapyramidal symptoms would have been unreported. It is unlikely that rare but serious possible adverse events associated with olanzapine use, such as dystonia or anaphylaxis, would have been observed in the relatively small number of children included in this study. Information regarding the presence of genetic polymorphisms that may predispose patients to olanzapine-induced weight gain was not available.111

3.6 Conclusion

Olanzapine, in conjunction with standard antiemetic prophylaxis with a 5-HT3 antagonist with/without dexamethasone, may be a promising, safe new intervention to improve CIV control in children. Prospective, controlled trials using validated pediatric nausea assessment tools are necessary to determine the extent of the contribution of olanzapine to CINV control and its safety profile in this population.

Table 3.1 Demographic data for 60 patients receiving olanzapine for chemotherapy-induced nausea and vomiting control during 158 chemotherapy blocks Sex (number of patients; M:F) 29:31 Diagnosis (number of patients; %) Osteosarcoma 16 (27) Neuroblastoma 12 (20) Other sarcomas 8 (13) Brain tumors 7 (12) Acute lymphoblastic leukemia 6 (10) Rhabdomyosarcoma 6 (10) Othera 5 (8) Median actual body weight at beginning of each chemotherapy 44.6 (12.2 to 89.1) block (kg; range) Median patient age at beginning of each chemotherapy block 13.2 (3.10 to 17.96) (years; range) Median time from cancer diagnosis at time of administration of 3.2 (0.1 to 90.9) first chemotherapy block during which olanzapine was given (months; range) aHodgkin Lymphoma, Non-Hodgkin Lymphoma, Rosai Dorfman disease, germ cell tumor

Table 3.2 Description of 158 chemotherapy blocks during which olanzapine was given for CINV control Chemotherapy Median duration of chemotherapy block (days; range) 4 (1 to 42)a Chemotherapy emetogenicity (number of blocks; %) High 128 (81) Moderate 28 (18) Low 2 (1) Minimal 0 Number of chemotherapy blocks containing cisplatin (%) 32 (20) Antiemetic Prophylaxis Provided Antiemetic agents given on a scheduled basis (number of blocks; %) Ondansetron or granisetron 154 (97) Dexamethasone 90 (57) Aprepitant 26 (16) Nabilone or dronabinol 21 (13) Lorazepam 15 (9) Scopolamine 7 (4) Promethazine 4 (3) Diphenhydramine 2 (1) Antiemetic agents given on an as needed basis (number of blocks; %) Lorazepam 103 (65) Hydroxyzine 65 (41) Dimenhydrinate 14 (9) Ondansetron or granisetron 15 (9) Promethazine 8 (5) Diphenhydramine 4 (3) Dronabinol or nabilone 4 (3) a One patient received daily oral temozolomide for 42 days.

Table 3.3 Description of olanzapine use during 158 chemotherapy blocks Reason for olanzapine use (number of blocks; %) History of uncontrolled CINV in previous chemotherapy block 94 (59) Unknown 37 (23) Uncontrolled CINV in current chemotherapy block 27 (17) Median number of chemotherapy blocks per patient during which olanzapine was given (range) 2 (1 to 10) Olanzapine dose frequency (number of blocks; %) Once daily 151 (96) Twice daily 7 (4) Mean initial single olanzapine dose ± standard deviation (range) mg/kg/dose 0.10 ± 0.051 (0.026 to 0.256)

mg/m2/dose 3.0 ± 1.45 (0.81 to 6.42)

Table 3.4 Vomiting control and adverse events reported in 158 chemotherapy blocks during which olanzapine was given Acute CIV control when olanzapine was initiated on the first day of chemotherapya (number of blocks; %) Highly emetogenic chemotherapy therapy (106 chemotherapy blocks) Complete CIV control 72 (68) Partial CIV control 23 (22) Uncontrolled CIV 11 (10) Moderately emetogenic chemotherapy (20 chemotherapy blocks) Complete CIV control 9 (45) Partial CIV control 3 (15) Uncontrolled CIV 8 (40) Low emetic risk chemotherapy (2 chemotherapy blocks) Complete CIV control 2 (100) Partial CIV control 0 Uncontrolled CINV 0 Reported adverse events (number of blocks; %) Sedation 11 (7) Increased transaminase concentrationsb 5 (20) Dizziness 2 (1) Hiccups 2 (1) Constipation 1 (0.6) Excessive hunger 1 (0.6) Fainting 1 (0.6) Hypertension 1 (0.6) Hyperglycemia 1 (0.6) Increased plasma creatinine concentration 1 (0.6) Stomach pain 1 (0.6) Mean change in weight between chemotherapy blocksc (%) 0 (-22 to +18) a assessed in 128 chemotherapy blocks, b assessed in 25 chemotherapy blocks where transaminase concentrations were assessed at least twice, c assessed in 26 patients who received olanzapine during more than 1 chemotherapy block 6 weeks or less apart

Chapter 4: Discussion and Conclusions

4.1 Summary of Key Findings

Both of these projects were undertaken with the intention of determining if it would be reasonable to further evaluate the use of olanzapine as an antiemetic agent in children. The results of both the systematic review and retrospective review complement each other well and support the conduct of future rigorous, controlled trials to further evaluate the role of olanzapine for the treatment and/or prevention of CINV in children.

The results of the systematic review and meta-analysis provided valuable information regarding the safety of olanzapine in young children. This review summarized the adverse effects associated with olanzapine use in 387 children ranging in age from 0.6 to 18 years described in 47 studies. Patients in these studies most often received olanzapine over a course of weeks to months for behavioural or psychiatric conditions and the dose ranged from 0.5-60 mg per day (often titrated based on efficacy and patient tolerability and excluding those reports of olanzapine poisoning or overdose). No deaths were attributable to olanzapine in any of the studies included and potentially serious adverse events, including extrapyramidal symptoms and neuroleptic malignant syndrome, were uncommon and reversible. Electrocardiogram abnormalities, blood glucose abnormalities and abnormalities in liver function tests were also uncommon. Sedation and weight were found to be the most commonly reported adverse effects.

These results provided reassurance regarding the safety of further investigations into the use of olanzapine for CINV in children. Sedation and weight gain, which were the most commonly reported adverse events, may actually be viewed in a positive light in patients receiving cancer treatment. Although olanzapine appears tolerable in children receiving it for psychiatric and or behavioural disorders, it is important to remember that the same may not be true in children who may receive it for prevention of CINV. For example, children with cancer often receive multiple medications in addition to chemotherapy which may interact with and/or affect the metabolism of other medications. Bearing these cautions in mind, the overall results of this review support future rigorous evaluation of the efficacy and safety of olanzapine as an antiemetic agent in

84 pediatric patients and highlight the need for its evaluation in a wide variety of children with cancer.

To our knowledge, the retrospective review is the first published study describing the use of olanzapine for the treatment and prevention of CINV in children. Complete control of CIV, defined as no episodes of vomiting or retching during the acute phase, was achieved in 83 of 128 (65%) chemotherapy blocks where olanzapine was initiated on the first day of chemotherapy (in addition to the antiemetics patients were already receiving as ordered by their primary care team). This control rate is quite good considering most patients were started on olanzapine secondary to a history of uncontrolled CINV during a previous chemotherapy block and it is more challenging to achieve complete CINV control in patients who have had uncontrolled nausea and vomiting in the past.5,103,112 Unfortunately nausea control was unable to be evaluated since nausea was not reported routinely or consistently in patients’ health records.

Sedation (11/158; 7%) and increased plasma transaminase concentrations (5/25; 20%) were the most common adverse effects reported during olanzapine use. Very few additional adverse effects were reported and they were of minor clinical significance.

The dose of olanzapine administered to patients was at the discretion of each prescriber and ranged from 0.026-0.256mg/kg/dose. This wide range highlights the fact that prescribers were unsure of the most appropriate pediatric dose to use for this indication. The mean initial single olanzapine dose was 0.10 ±0.051mg/kg/dose. There was no association between the olanzapine dose/kg and complete CIV control (OR 1.01; 95% CI: 0.999-1.020; p = 0.091). However, increasing olanzapine dose was significantly associated with sedation (OR 1.17; 95% CI: 1.08- 1.27; p = 0.0001).

Overall, good CIV control rates appear achievable with the addition of olanzapine to standard antiemetic prophylaxis and the use of olanzapine in children receiving chemotherapy for the treatment of cancer appears safe.

4.1.1 Safety Findings

Emphasis can be placed on the safety results generated from both projects. Sedation was the most commonly reported adverse effect and no major safety concerns were highlighted in either study. A well-designed, prospective study should be completed in order to appropriately evaluate olanzapine for CINV control in children. The studies presented in this thesis provide reassurance that safety concerns do not present an immediate barrier such studies. Furthermore, the observations of good CINV control in the retrospective review are a signal that the potential benefits of olanzapine make future trials more compelling.

Our findings regarding the low risk of serious adverse effects associated with the use of olanzapine in children are not surprising considering what has been previously reported in the literature for adults and adolescents receiving this medication. Adverse effects most commonly reported for adults receiving olanzapine chronically for psychiatric conditions include weight gain, sedation, EPS, liver function test abnormalities, and increases in glucose, prolactin, triglyceride and/or cholesterol concentrations in the blood.19 Similar adverse effects have been reported in adolescents with a potential increased risk in this population for weight gain, and elevated blood glucose, prolactin, triglyceride and cholesterol concentrations.

It is possible that a different adverse effect profile may be observed in patients receiving olanzapine for CINV. Patients receiving the medication for treatment or prevention of CINV would receive olanzapine for a short period of time (days) while receiving chemotherapy as opposed to those patients who receive the medication for psychiatric conditions chronically (over months to years). The dose is often titrated to an optimal effective dose based on patient tolerability in patients receiving it for psychiatric conditions. Titration would not be practical in patients receiving olanzapine for CINV considering the short duration of use. In addition, patients receiving olanzapine for CINV receive several concomitant medications, including chemotherapy, antibiotics, and antifungals, and it is unknown whether there are potential significant drug interactions in this population. Olanzapine is primarily metabolized via the cytochrome P450 1A2 pathway and, therefore, precautions should be taken if it is to be co- administered with medications which may induce (for example carbamazepine) or inhibit (for example, ciprofloxacin) this enzymatic pathway. The significance of potential interactions with

86 chemotherapy specifically and other medications used commonly in pediatric cancer patients remains to be determined.

Studies evaluating the use of olanzapine as an antiemetic agent in adult cancer patients have not reported concerning adverse effects associated with its use. One study evaluating the use of olanzapine for the treatment of breakthrough CINV compared to metoclopramide specifically reported no Grade III or IV toxicities with olanzapine use.31 In an additional study, 73% of patients described sleepiness during chemotherapy while receiving olanzapine plus a 5-HT3 antagonist (azasetron) and dexamethasone.32 However, there was no comparison made with respect to sleepiness with the control group who received azasetron and dexamethasone. There were also no differences in blood glucose concentrations, lipid concentrations, or patients’ weight in the adult cancer patients included in both the olanzapine and comparator arm of this study and once again no Grade III or IV toxicities were observed.32 Overall, the few reports of adverse effects in adult oncology patients receiving olanzapine for short periods of time are of mild clinical significance and reversible.

Similar to what has been observed in adult oncology trials, patients included in our retrospective review experienced few adverse effects. Sedation was the most commonly reported problem. Adverse effects that were reported were of minor clinical significance and transient, which parallels reports in adults with cancer thus far.

4.1.2 Efficacy Findings

As previously mentioned, there are multiple reports in the literature of the safe and effective use of olanzapine as an antiemetic in adults with cancer. It has been used both as a treatment option for patients experiencing breakthrough or refractory CINV and as prophylaxis for prevention of CINV.

Most studies published regarding the use of olanzapine as an option for the treatment of breakthrough CINV have been conducted by Navari et al. His group has published multiple

87 randomized controlled trials evaluating the efficacy of olanzapine in this setting in adults with cancer with positive results.28-31 His most recently published study compared the use of olanzapine to metoclopramide for the treatment of breakthrough CINV in 108 adults.31 Over the 72 hour observation period, 70% (39/56) of patients receiving olanzapine experienced no emesis while 31% (16/52) of patients receiving metoclopramide experienced no emesis (P<0.01). Complete control of nausea during this time period was achieved by 68% (38/56) of patients in the olanzapine group and 23% (12/52) patients in the metoclopramide group. Overall, patients receiving olanzapine had better complete control of nausea and vomiting than those receiving metoclopramide.

Navari et al also evaluated the use of olanzapine as a prophylactic antiemetic agent in comparison to aprepitant in 221 adults with cancer.30 A complete overall response, defined as no emesis and no use of rescue medications, was observed in 77% of patients in the olanzapine group compared to 73% of patients in the aprepitant group (p>0.05). However, the most impressive results relate to nausea control during the delayed phase: 69% of patients in the olanzapine group achieved complete control of nausea during the delayed phase compared to 38% of patients in the aprepitant group (p<0.01).

Tan et al evaluated the efficacy of the addition of olanzapine to standard antiemetic prophylaxis in 229 adult cancer patients.32 Similar to what was observed by Navari et al., significant improvements in complete control of nausea during the delayed phase were observed in the olanzapine group compared to the comparator arm (70% vs. 30% respectively; p<0.05) for those patients receiving highly emetogenic chemotherapy).

A complete vomiting control rate was achieved in 83 of 128 chemotherapy blocks (65%) in our retrospective review. This control rate is similar to what has been observed in the studies published in adults. Unfortunately we were unable to evaluate the efficacy of olanzapine related to nausea or overall CINV control due to the retrospective nature of our study design and since nausea is not routinely recorded in patients’ charts. Based on the adult literature, it appears this is where this agent may prove most beneficial and future trials evaluating its efficacy in children for nausea control are warranted.

4.2 Strengths and Limitations

Our work investigating the use of olanzapine as an antiemetic option in children is novel and important. Prior to publication of these projects, there was no information in the literature describing the use of olanzapine as an antiemetic option in children. As previously described, new antiemetic strategies are required to improve care for pediatric patients as control of CINV remains suboptimal with the current available options.

The largest specific strength of these projects was our ability to use two different and complementary approaches to evaluate the safety of olanzapine in children. Our inclusion criteria for the systematic review were broad so that a comprehensive summary of all possible adverse events experienced by children could be provided. However, no studies included in this review included pediatric cancer patients. In contrast, although our retrospective review may be considered a less rigorous study design, it allows for direct application of the results to children with cancer receiving chemotherapy as this was the population studied in this review.

An additional strength of this research is the original contribution to the literature. Multiple research gaps were identified which warrant further exploration in order to optimize supportive care for pediatric cancer patients. These gaps include the need to prospectively determine the optimal olanzapine dose for CINV prevention and/or treatment in pediatric patients, the safety of this agent in children with cancer specifically, and its optimal place in therapy (CINV prophylaxis vs treatment). Completion of these projects is an example of the incremental steps that should be considered to ensure the safe conduct of rigorous, randomized, controlled trials in vulnerable populations.

Overall, both projects included in this thesis provide a starting point for future evaluations of the use of olanzapine for CINV in children with cancer. Completion of large, controlled, well- designed studies in pediatric patients is challenging. It may be argued that a randomized controlled trial of olanzapine in pediatric cancer patients may not be necessary based on the efficacy data available in adults and from the retrospective review as well as the safety information from the systematic review and retrospective review included in this thesis. Although the information provided in these studies is reassuring, I would be hesitant to

89 recommend the routine incorporation of olanzapine as a standard of care antiemetic agent for children with cancer without prospective evaluation of its use in this setting.

Too often drugs are incorporated into pediatric practice without strong evidence to support their efficacy and safety. Since children respond to drugs differently than adults and have different drug-related needs than adults, this situation has left children open to an increased risk of drug- related harm and to a decreased chance of having their specific drug-related needs met. Rather than accepting the information learned through the information provided in this thesis as sufficient to permit safe and effective CINV prophylaxis with olanzapine in children receiving chemotherapy, I believe the information is best used to inform safety monitoring requirements and to guide dosing recommendations in future pediatric trials. Furthermore, our findings highlight the need to balance dose-related adverse effects, such as sedation, with efficacy. Results from a randomized, placebo-controlled trial evaluating the use of olanzapine for CINV prophylaxis in children with cancer would support a strong recommendation for or against its use as an antiemetic in pediatric cancer patients.

4.3 Recommendations for Future Research

The projects presented in this thesis have set a solid foundation for future work evaluating the use of olanzapine as an antiemetic agent in children; however, a tremendous amount of work remains to be done for this agent to be incorporated into the standard of care for children with cancer. We are hopeful that a large placebo-controlled trial will help clarify the role of olanzapine as an antiemetic in children. For example, it will be important to determine whether olanzapine is best suited for CINV prevention or for CINV treatment in children. It will also be valuable to determine at which phase (for example acute vs delayed) olanzapine confers the most benefit in children. In addition, evaluation of the impact of olanzapine on nausea control, using validated pediatric tools such as the Pediatric Nausea Assessment Tool (PeNAT) or the Baxter Retching Faces scale (BARF), is required. 113,114

Based upon the two studies presented in this thesis, the specific course of future studies is as follows. First, a feasibility study should be completed to determine whether or not a randomized,

90 placebo-controlled trial can be conducted. This study would provide baseline information including data which would inform additional safety monitoring requirements and an appropriate starting dose of olanzapine for CINV prevention in children. If deemed feasible, a larger, randomized, placebo-controlled trial should be carried out in order to more rigorously evaluate the safety and efficacy of olanzapine specifically in pediatric cancer patients and to assist with determining the optimal olanzapine dose to use for CINV control in children.

4.5 Conclusion

CINV control in children with cancer remains sub-optimal. Olanzapine may well offer the opportunity to improve CINV control and, in turn, the quality of life of these children. Based on the information provided in this thesis, future prospective trials evaluating the role of olanzapine for the prevention and treatment of CINV in pediatric patients are unlikely to pose significant risks of harm and are likely to convey benefit. The results of such trials will provide a high quality evidence base upon which recommendations can be formulated regarding the use of olanzapine for CINV control in pediatric patients.

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