Explorations of the use of Olanzapine for Management of … · 2015. 11. 29. · 1.1 Chemotherapy-induced Nausea and Vomiting Chemotherapy-induced nausea and vomiting (CINV) is one

Explorations of the use of Olanzapine for Management of

Chemotherapy-induced Nausea and Vomiting in Children

by

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

© Copyright by Jacqueline Flank 2015

ii

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.

iii

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.

iv

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

v

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

vi

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

vii

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

viii

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

ix

OR Odds ratio

PeNAT Pediatric Nausea Assessment Tool

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT Randomized-controlled trial

1

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.

2

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.

3

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.

5

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-

6

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

7

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.

8

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

9

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.

15

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.

16

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.

17

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.

20

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.

21

Figure 2.1 Literature Search Flow Chart

22

Figure 2.2 Forest Plots

2.2A Blood Glucose Abnormalities

2.2B Electrocardiogram (ECG) Abnormalities

23

2.2C Extrapyramidal Symptoms

2.2D Liver Function Test (LFT) Abnormalities

24

2.2E Sedation

2.2F Weight gain

25

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)")


7. 4 or 6

Embase Classic+Embase 1947 to 2013 Week 39

1. olanzapine/

2. limit 1 to (infant <to one year> or child <unspecified age> or preschool child <1 to 6 years>

or school child <7 to 12 years>





relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav).tw.


pediatric*).mp.

6. 4 and 5


8. 3 or 7

26

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




relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav).mp.


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


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

pediatric*)


# 1 TS=(Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or



relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav)


27

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"))

28

Table 2.2 Characteristics of Included Studies

Author Year

Pub

Study Design Risk of Bias in

Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )

Diagnosis Mean Olanzapine Dose

± Standard Deviation

(range)

Duration of

Olanzapine

Treatment

Hollander 2006 RCT Moderate 6 9.25±2.9yrs

(6-14.8yrs)

Pervasive developmental

disorder

10±2.04mg/day

(7.5-12.5mg/day)

8 weeks

Shaw 2006 RCT Low 13 12.8±2.4yrs

(6-17yrs)

Childhood-onset

schizophrenia

18.1±4.3mg/day

(5-20mg/day)

8 weeks

Wozniak 2009 Prospective,

open-label

comparison

Moderate 17 10.2±2.6yrs

(6-17yrs)

Bipolar disorder

8.6±3.4mg/day

(olanzapine group)

(7.5-12.5mg/day)

8 weeks

Fido 2008 Prospective,

open-label


(7-17yrs)

Autism

7.5mg/day

(5-10mg/day)

13 weeks

McCracken 2008 Prospective,

open-label


(7-14yrs)

Tourette syndrome

11.3±5.6mg/day

(2.5-20mg/day)

6 weeks

Quintana 2007 Prospective,

open-label


(8-17.9yrs)

Schizophrenia

6.8±6.41mg/day (female

participants)

8.33±4.51mg/day (male

participants)

(2.5-20mg)

9 weeks

Milin 2006 Prospective,

open-label


(10-15yrs)

Asperger disorder

8.25mg/day

(5-15mg/day)

12 weeks

29

Author Year

Pub


Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )



(range)

Duration of

Olanzapine

Treatment

Mozes 2006 Prospective,

open-label

comparison

Low 12 11.5±1.64yrs

(9-14yrs)

Childhood-onset

schizophrenia

8.18±4.41mg/day

(2.5-20mg/day)

12 weeks

Sethi 2006 Prospective,

open-label

High 6 median: 9yrs

(5-13yrs)

Sydenham chorea

5.8mg/day

(5-10mg/day)

3-4 months

Biederman 2006 Prospective,

open-label

comparison

Moderate 15 5±0.8yrs

(4-6yrs)

Bipolar disorder

6.3±2.3mg/day

(1.25-10mg/day)

8 weeks

Stephens 2004 Prospective,

open-label


(7-13yrs)

Tourette syndrome

14.5mg/day

(1.25-20mg/day)

8 weeks

Mozes 2003 Prospective,

open-label


(11-14yrs)

Childhood-onset

schizophrenia

15.56±4.64mg/day

(10-20mg/day)

10 weeks

Ross 2003 Prospective,

open-label


(6-15yrs)

Childhood-onset

Schizophrenia

5.1±2.2mg/day (week 3)

6.1±3.6mg/day (week 6)

7.7±4.1mg/day at (3

months) 9.3±4.7mg/day

(6 months)

10.4±3.5mg/day (1 year)

Up to 1 year

Kemner 2002 Prospective,

open-label

Moderate 25 mean: 11.22yrs

(6.4-16.6yrs)

Pervasive developmental

disorder

10.7mg/day

(2.5-20mg/day)

12 weeks

Frazier 2001 Prospective,

open-label


(5.4-14.7yrs)

Acute mania

9.6±4.3mg/day

(2.5-20mg/day)

8 weeks

30

Author Year

Pub


Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )



(range)

Duration of

Olanzapine

Treatment

Malone 2001 Prospective,

open-label

comparison

High 6 8.5±2.4yrs

(4.9-11.8yrs)

Autism

7.9±2.5mg/day

(5-10mg/day)

6 weeks

Sholevar 2000 Prospective,

open-label

High 15 9.4±1.99yrs

(6-13yrs)

Childhood-onset

schizophrenia

4.8mg/day

(2.5-5mg/day)

Mean: 11.3

days

Turkel 2013 Retrospective

review

High 16 1.7±0.67yrs

(0.58-2.8yrs)

Delirium

4.81±5.76mg/day

(0.5-23mg/day)

Mean: 39±41.4

days

(Range: 2-

151days)

Turkel 2012 Retrospective

review

High 78 10.8±4.9yrs

(1-18yrs)

Delirium

10mg/day

(0.625-60mg/day)

Mean: 26.5

days

(Range: 1-

132days)

Taskiran 2013 Case report N/A 1 7.5yrs Pervasive developmental

disorder

15mg/day

2 months

Bozkurt 2010 Case report N/A 1 11yrs Catatonia

5mg/day

Not reported

Herguner 2010 Case report N/A 1 6yrs Autistic disorder

2.5-7.5mg/day

Not reported

Ferreira Maia 2007 Case report N/A 1 10yrs Bipolar disorder

15mg/day

Not reported

Emiroglu 2006 Case report N/A 1 8yrs Bipolar disorder

15mg/day

6 months

31

Author Year

Pub


Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )



(range)

Duration of

Olanzapine

Treatment

Beresford 2005 Case report N/A 1 4.25yrs Schizophreniform

disorder

8.75mg/d (↓ to

3.75mg/day after 1

month)

Not reported

Chungh 2005 Case report N/A 1 12yrs Bipolar disorder and mild

mental retardation

2.5mg/day

2 days

Courvoisie 2004 Case report N/A 1 7yrs Attention deficit

hyperactivity disorder,

bipolar disorder, and

oppositional defiant

disorder

2.5mg/day

Approx. 9

months

Ercan 2004 Case report N/A 1 12yrs Schizophrenia

5-15mg/day

Not reported

Boachie 2003 Case series N/A 4 11yrs

(10-12yrs)

Anorexia nervosa

2.5mg/day

Not reported

Sheikh 2002 Case report N/A 1 10yrs Acute agitation and

attention deficit

hyperactivity disorder

2.5-7.5mg/day

15 days

Mehler 2001 Case report N/A 1 12yrs Anorexia nervosa

5mg/day

Not reported

Nguyen 2001 Case report N/A 1 10yrs Attention deficit

hyperactivity disorder

5mg/day

Several months

(specific time

frame not

reported)

32

Author Year

Pub


Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )



(range)

Duration of

Olanzapine

Treatment

Bengi Semerci 2000 Case report N/A 1 9yrs Tourette’s disorder

5mg/day, increased to

10mg/day after one week Not reported

Chang 2000 Case series N/A 3 10.3yrs

(9-12yrs)

Acute mania

2.5-5mg/day

1-3months

Lavid 1999 Case reports N/A 2 9.5yrs

(9-10yrs)

Stuttering

1.25-2.5mg/day

2-5mths

Krishnamoorthy 1998 Case series N/A 5 9.2yrs

(6-11yrs)

Psychiatric disorder

7.5mg/day

(2.5-10mg/day)

14-52 days

Malek-Ahmadi 1998 Case report N/A 1 8yrs Hyperactivity and

aggressive behaviour

5-7.5mg/day

Not reported

Horrigan 1997 Case reports N/A 2 9.5yrs

(9-10yrs)

Bipolar disorder, mental

retardation, and autistic

behaviour

5-20mg/day

Not reported

Hail 2013 Case report

(overdose)

N/A 1 6yrs Not applicable

75-100mg

Not applicable

Tanoshima 2013 Case report

(overdose)

N/A 1 1.4yrs Not applicable

20-50mg

Not applicable

Lankheet 2011 Case report

(overdose)


Reported: 30mg

Estimated based on

levels: 115-230mg Not applicable

Kochhar 2002 Case report

(overdose)


210mg

Not applicable

33

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

Author Year

Pub


Measurement of

Adverse Effects

N Mean Age ±

Standard

Deviation

(range )



(range)

Duration of

Olanzapine

Treatment

Bond 1999 Case report

(overdose)


10mg

Not applicable

Bonin 1999 Case report

(overdose)

N/A 1 1yr Not applicable

Unknown

(level = 340ng/mL) Not applicable

Catalano 1999 Case report

(overdose)


30-40mg

Not applicable

Chambers 1998 Case report

(overdose)


100mg

Not applicable

Yip 1998 Case report

(overdose)


7.5-15mg

Not applicable

34

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

Author Study Aim Patient

Characteristics

Olanzapine Dose Length of

Treatment

Adverse

Effects

Monitored

Adverse Effects Reported Comments

Randomized Controlled Trials

Hollander

(2006)

Determine

efficacy of

olanzapine for

treatment of

pervasive

developmental

disorder vs

placebo

G1

(olanzapine):

N = 6

age: 6-14.8yrs

(mean:

9.25±2.9yrs)

M:F = 6:0

G2 (placebo):

N = 5

age: 6.1-11yrs

(mean:

8.9±2.1yrs)

M:F = 3:2

Mean:

10±2.04mg/day

Range: 7.5-

12.5mg/day

doses titration:

<40kg: 2.5mg every

other day for 3 days,

then 2.5mg daily

>40kg: 2.5mg daily

for 3 days, then 5mg

daily

doses in both weight

groups ↑ in 5mg

increments weekly

max = 20mg/day

8 weeks Baseline: BP,

CBC,

chemistry

profile, height,

LFTs, pulse,

urinalysis,

weight

Follow-up:

adverse

effects, BP,

EPS, height,

pulse weight

G1:

↓ Appetite: 1/6

↑ Appetite: 3/6

Constipation: 3/6

EPS:0/6

Glazed eyes: 1/6

Headache: 1/6

Insomnia: 1/6

Nervousness: 0/6

Rhinitis: 1/6

Sedation: 4/6

Thirst: 0/6

Weight gain: 5/6

(mean: 3.4±2.2kg)

Follow-up occurred

weekly x 4weeks, then

biweekly x 4 weeks

Adverse effects

reported using the

“Olanzapine Side

Effect Checklist”

EPS monitored using

the AIMS, Tardive

Dyskinesia Rating

Scale, and Barnes

Akathesia score

35


Characteristics


Treatment

Adverse

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

(2006)

Compare

efficacy and

safety of

olanzapine and

clozapine in

children with

G1

(olanzapine):

N = 13

Age: 6-17yrs

(mean:

12.8±2.4yrs)

Mean:

18.1±4.3mg/day

Range: 5-20mg/day

dose titration: 5mg

8 weeks Baseline:

BMI, CBC,

ECG, EEG,

electrolytes,

LFTs

G1:

↓ ANC: 1/13

↑ Appetite: 4/13

1 pt receiving

olanzapine withdrew

during week 2 (was

receiving 5mg daily) –

reason not specified

36


Characteristics


Treatment

Adverse

Effects

Monitored


childhood-onset

schizophrenia

M:F = 7:6

G2 (clozapine):

N = 12

Age: 6-17yrs

(mean:

11.7±2.3yrs)

M:F = 8:4

daily, ↑to 10mg on

approx day 12, then

↑to 15mg at week 3

Further ↑guided by

clinical judgment

max = 20mg/day

Weekly:

adverse

effects, CBC,

EPS

Week 6: ECG,

EEG,

electrolytes,

LFTs

Study

completion:

BMI

↑ BMI: proportion of patients

not reported (mean: 1.4±1.6)

Constipation: 4/13

Difficulty Concentrating:

1/13

ECG abnormalities: 1/13

Enuresis: 1/13

Hypersalivation: 4/13

Hypertension: 1/11

Insomnia: 1/13

LFT abnormalities: 0/13

Somnolence: 2/13

Tachycardia (>100bpm): 2/12

Weight gain: proportion of

patients not reported

(mean: 3.6±4kg)

G2:

↓ANC: 2/12

Adverse effects

reported using the

Treatment Emergent

Symptom Scale Write-

In

EPS monitored using

the AIMS, and

Simpson Angus Scale

Authors reported “few

EPS symptoms”

experienced by

patients in both groups.

There was no

significant change in

AIMS or Simpson

Angus scales from

baseline over the

course of the study.

All patients with ECG

abnormalities were

deemed fit to continue

in the study by

cardiologist

37


Characteristics


Treatment

Adverse

Effects

Monitored


↑ Appetite: 4/12

↑ BMI: proportion of patients

not reported (mean: 1.6±2.5)

Constipation: 2/12

Difficulty Concentrating:

4/12


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


Somnolence: 3/12

38


Characteristics


Treatment

Adverse

Effects

Monitored


Tachycardia (>100bpm): 8/10


patients not reported

(mean: 3.8±6kg)

Prospective single-blind/open-label/naturalistic studies


Characteristics


Treatment

Adverse

Effects

Monitored


Wozniak

(2009)

Determine if co-

administration of

topiramate with

olanzapine

results in less

weight gain and

clinical

improvement vs

olanzapine

monotherapy in

children with

bipolar disorder

G1

(olanzapine):

N = 17

Age: 6-17yrs

(mean:

10.2±2.6yrs)

M:F = 10:7

G2 (olanzapine

+ topiramate):

N = 23

Age: 6-17yrs

(mean:

9.7±2.8yrs)

M:F = 11:12

G1:

Mean:

8.6±3.4mg/day

G2:

Mean:

9.9±5.2mg/day

Range: 7.5-

12.5mg/day

dose titration: 2.5mg

daily, ↑ weekly as

tolerated by 2.5-5mg

max = 20mg/day


BG, lipid

levels,

prolactin, and

weight

Weekly:

adverse

effects, BP,

weight

Study

completion:

adverse

effects, BG,

BP, lipid

levels,

G1:

Aches & Pains: 1/17

Agitation/activation: 2/17

Anxiety: 1/17

↑ Appetite: 12/17

Cold/flu/allergies/infection:

4/17

Depression: 0/17

Dry eyes, nose, or mouth:

1/17

4 patients from G1

withdrew – 2 withdrew

due to adverse effects

(1 patient ↑ appetite, 1

patient tremor)

Common

spontaneously reported

symptoms included

increased appetite,

cold symptoms,

sedation, and headache

39


Characteristics


Treatment

Adverse

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


4.7ng/dL)

Sedation: 7/17

Sleep problems: 0/17

Skin Disturbance:1/17

Tics: 1/17

Urinary adverse effects: 0/17

40


Characteristics


Treatment

Adverse

Effects

Monitored




5.3±2.1kg)

G2:

Aches & Pains: 3/23


Anxiety: 0/23

↑ Appetite: 10/23

↑ Cholesterol: proportion of


0.63mmol/L)


4/23

Depression: 1/23


0/23

GI problems: 3/23

↑ HDL: proportion of patients

not reported (mean:

0.2mmol/L)

41


Characteristics


Treatment

Adverse

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



16.9bpm)

Sedation: 3/23

Sleep problems: 1/23

Skin Disturbance: 1/23

Tics: 0/23

↑ Triglycerides: proportion of


0.76mmol/L)




2.6±3.6kg)

42


Characteristics


Treatment

Adverse

Effects

Monitored


Fido

(2008)

Determine the

efficacy and

safety of

olanzapine for

the treatment of

children with

autism

N = 40

Age: 7-17yrs

(mean:

12.2±2.2yrs)

M:F = 40:0

Mean: 7.5mg/day

Range: 5-10mg/day


twice daily for 1

week, dose then ↑(or

↓) in increments of

2.5mg

max = 10mg/day

13 weeks Baseline: BG,

chest X-ray,

ECG, EPS,

hematology,

hepatitis B

serology, lipid

profile, serum

chemistry,

urinalysis,

weight

Study

completion

(13 weeks):

BG, chest X-

ray, ECG,

EPS,

hematology,

hepatitis B

serology, lipid

profile, serum

chemistry,

urinalysis,

weight

Drowsiness/sedation: 5/40

EPS: 4/40




0.25kg)

EPS monitored using

the AIMS

No significant change

in AIMs score from

baseline to week 13

(all 4 patients with

EPS had similar scores

at baseline)

Drowsiness/sedation

reported when

treatment initiated but

not present by week 13

No significant changes

in lab values measured

McCracken

(2008)

Determine the

efficacy and

safety of

olanzapine for

the treatment of

Tourette

Syndrome

N = 12

Age: 7-14yrs

(mean:

11.33±2.35yrs)

M:F = 11:1

Mean:

11.3±5.6mg/day

Range: 2.5-20mg/day

dose titration:

<40kg: 2.5mg every

other day for 3 days,

then 2.5mg daily for

6 weeks Baseline:

ECG,

hematology,

clinical

chemistry,

urinalysis,

weight

Drowsiness: 12/12



13bpm)

Weight gain: 12/12 (mean:

4kg, range: 1.1-7.7kg)

Adverse effects


and monitored weekly

by physical

examination

Sedation and increased

appetite frequently

reported

43


Characteristics


Treatment

Adverse

Effects

Monitored


4 days, then 5mg

daily for 1 week,

then ↑ in 5mg

increments as needed

>40kg: 2.5mg daily

for 3 days, then 5mg

daily for 4 days, then

↑ in 5mg increments

as needed

max = 20mg/day

Weekly:

adverse effects

Study

completion

(week 6):

adverse

effects,

hematology,

clinical

chemistry,

urinalysis,

weight

No clinically

significant changes

from baseline in lab

values (all values

remained within

normal limits for age)

Quintana

(2007)

Evaluate the use

of olanzapine for

the treatment of

children and

adolescents with

schizophrenia

N = 16

Age: 8-17.9yrs

(mean:

12.9±2.48yrs)

M:F = 9:7

Mean (F):

6.8±6.41mg/day

Mean (M):

8.33±4.51mg/day

Mean mg/kg dose:

0.17mg/kg

Range: 2.5-20mg


daily, then ↑ (or ↓) in

increments of 2.5mg

ever 4-8 days

max = 20mg/day


CBC,

chemistry

profile, EPS,

HCG (if of

childbearing

potential),

pulse,

urinalysis,

weight

Weekly:

adverse

effects, BP,

EPS, pulse,

weight

Study

EPS: 3/16



6.18±3.87kg)

EPS monitored using

the AIMS

12/16 patients

completed all 10

follow-up assessments

– NO dropouts due to

adverse effects

Patients who

experienced EPS

received olanzapine

15-20mg/day

No clinically

significant changes

from baseline for BP,

ECG, pulse, BG, or

44


Characteristics


Treatment

Adverse

Effects

Monitored


completion:

adverse

effects, BP,

CBC,

chemistry

profile, EPS,

HCG (if of

childbearing

potential),

pulse,

urinalysis,

weight

cholesterol/lipids when

evaluated

retrospectively

Milin

(2006)

Evaluate the use

of olanzapine for

the treatment of

children with

Asperger

Disorder

N = 10

Age: 10-15yrs

(mean:

12.6±2.02yrs)

M:F = 10:0

Mean = 8.25mg/day

Range = 5-15mg/day


daily, then ↑ in

increments of 2.5mg

weekly

max = 15mg/day

12 weeks Baseline:

ECG,

hematology,

physical exam

Every 4

weeks:

hematology

BG, ECG,

EPS, height

and weight

assessed at

random

intervals

↑ BG: 0/10


(not thought to be from

olanzapine)

EPS: 0/10



4.69kg)

Adverse Effects

monitored using a self-

report “side effects

checklist”

EPS monitored using

the AIMs

AIMs scored decreased

from baseline – related

to improvements in

stereotypic involuntary

movements associated

with children with

Asperger Disorder

2 patients withdrew

(12 patients enrolled,

10 evaluated) – exact

reasons for dropout not

reported

45


Characteristics


Treatment

Adverse

Effects

Monitored


Mean BMI within

normal parameters at

baseline and trial

completion

Fatigue, loss of

attentiveness, and

nausea commonly

reported

Mozes

(2006)

Compare

efficacy and

safety of

olanzapine vs

risperidone for

the treatment of

childhood-onset

schizophrenia

G1

(olanzapine):

N = 12

Age: 9-14yrs

(mean:

11.5±1.64yrs)

M:F = 5:7

G2

(risperidone):

N = 13

Age: 6-17yrs

(mean:

10.71±1.43yrs)

M:F = 5:8

Mean:

8.18±4.41mg/day

Range: 2.5-20mg/day


daily, then ↑ based

on clinical response

and adverse effects

max = 20mg/day


pulse, weight

Weekly: BP,

EPS, pulse,

weight

Study

completion:

BP, EPS,

pulse, weight

G1:

Akathisia: 3/12

EPS: 7/12



5.78±3.1kg)

G2:

Akathisia: 1/13

EPS: 8/13



4.45±2.87kg)

1 patient in olanzapine

group lost to follow-up

EPS/akathisia

monitored using the

Barnes Akathisia

Rating Scale and

Simpson-Angus Scale

46


Characteristics


Treatment

Adverse

Effects

Monitored


Sethi

(2006)

Evaluate the

efficacy of

olanzapine for

the treatment of

Sydenham

chorea

N = 6

Age: 5-13yrs

(median: 9yrs)

M:F = 2:4

Mean: 5.8mg/day

Range: 5-10mg/day

dose titration:

5mg daily, then ↑

based on clinical

response after 1

week

max = 10mg/day

3-4months Not reported No adverse effects observed 1 patient received a

dose of 10mg daily

(the remaining

patients received 5mg

daily)

Biederman

(2005)

Evaluate

olanzapine and

risperidone for

the treatment of

bipolar disorder

in preschoolers

G1

(olanzapine):

N = 15

Age: 4-6yrs

(mean:

5±0.8yrs)

M:F = 10:5

G2

(risperidone):

N = 16

Age: 4-6yrs

(mean: 5.3±0.8y

yrs)

M:F = 12:4

Mean:

6.3±2.3mg/day

Range: 1.25-

10mg/day

dose titration:

1.25mg daily, then ↑

weekly as tolerated

max = 10mg/day

8 weeks

Baseline: BG,

BP, lipid

levels,

prolactin,

weight

Weekly:

adverse

effects, BP,

weight

Study

completion:

adverse

effects, BG,

BP, lipid

levels,

prolactin,

weight

G1:

Aches & Pains: 1/15


Anxiety: 0/15

↑ Appetite: 9/15

Cardiovascular adverse

effects: 0/15


6/15

Drooling: 0/15


1/15

Adverse effects


1 olanzapine patient

withdrew due to

adverse effects (↑

appetite and hand

tremor)

Common reported

adverse effects

included ↑ appetite,

cold/flu like

symptoms, sedation,

and headache

47


Characteristics


Treatment

Adverse

Effects

Monitored


GI problems: 1/15

Headache: 2/15

Neurological adverse effects:

1/15



11.9ng/dL)



17bpm)

Respiratory adverse effects:

0/15

Sedation: 3/15





3.2±0.7kg)

G2:

Aches & Pains: 0/16

48


Characteristics


Treatment

Adverse

Effects

Monitored



Anxiety: 1/16

↑ Appetite: 8/16

↑ BP (systolic): proportion of


9.8)

Cardiovascular adverse

effects: 1/16


5/16

Drooling: 1/16


3/16

GI problems: 4/16

Headache: 5/16

Neurological adverse effects:

0/16



35.7ng/dL)

Respiratory adverse effects:

2/16

49


Characteristics


Treatment

Adverse

Effects

Monitored


Sedation: 4/16





2.2±0.4kg)

Stephens

(2004)

Evaluate the

efficacy of

olanzapine in

reducing

aggressive

behaviour in

children with

Tourette

Syndrome

N = 10

Age: 7-13yrs

(mean:

9.9±1.7yrs)

M:F = 9:1

Mean: 14.5mg/day

Range: 1.25-

20mg/day


daily for 2 weeks,

then ↑ to 5mg daily

for 2 weeks (if

tolerated), then ↑in

5mg increments bi-

weekly as tolerated

max = 20mg/day


clinical

chemistry,

ECG,

hematology,

height, pulse,

weight

Bi-weekly:

adverse

effects, BP,

clinical

chemistry,

ECG (at week

6 only),

hematology,

height, pulse,

weight

Study

completion:

adverse

effects, BP,

clinical

Akathisia: 0/10

↑ ALP: proportion of patients

not reported (mean ↑ of 26.8)

Anxiety: 0/10

↑BP: 0/10

Cognitive blunting: 0/10

Constipation: 0/10

Diarrhea: 0/10

Dizziness: 0/10

Dry mouth: 1/10


EPS: 0/10

Fatigue: 4/10

Adverse effects

spontaneously

reported and actively

monitored using

adverse symptom

checklist

EPS monitored using

the AIMS, and

Simpson Angus Scale

ALP values remained

within normal limits

for age

Fatigue associated with

dose ↑ and resolved for

most patients over time

50


Characteristics


Treatment

Adverse

Effects

Monitored


chemistry,

ECG,

hematology,

height, pulse,

weight

Headache: 5/10

Psychomotor slowing: 0/10



5.4±2.6kg)

Mozes

(2003)

Evaluate the

efficacy of

olanzapine for

the treatment of

childhood-onset

schizophrenia

resistant to

typical

antipsychotics

N = 9

Age: 11-14yrs

(mean:

12.5±1.13yrs)

M:F = 10:0

Mean:

15.56±4.64mg/day

Range: 10-20mg/day


daily for 4 days, then

↑ to 5mg daily for

approx. 2 weeks,

then ↑in 5mg

increments

max = 20mg/day

10 weeks Baseline: BG,

CBC, general

serum

chemistry,

ECG, EEG,

kidney

function tests,

LFTs, physical

exam,

urinalysis

Weekly: BP,

CBC, EPS,

LFTs, weight


EPS: 0/9

↑LFTs: 0/9

Somnolence: 7/9


6.1±3.25kg)

No scale used to

measure EPS -

monitored by clinical

examination

ECG and EEG

repeated once during

olanzapine treatment

No adverse changes

seen in blood

chemistry,

hematological, or EEG

parameters

Ross

(2003)

Evaluate the

efficacy of

olanzapine for

the treatment of

childhood-onset

schizophrenia

N = 19

Age: 6-15yrs

(mean:

10.5±2.4yrs)

M:F = 14:5

Mean:

5.1±2.2mg/day at 3

weeks,

6.1±3.6mg/day at 6

weeks,

7.7±4.1mg/day at 3

months,

9.3±4.7mg/day at 6

months,

10.4±3.5mg/day at 1

year

Up to 1

year

All

participants:

height, weight

at each follow-

up visit

Final 10

subjects to

enroll:

↑BG: 0/10

↑BMI: 10/19

EPS: 0/10

Temperature change: 0/19



1.6kg in 1st 3 weeks, 3.8kg

Recruitment focused

on patients 12 and

under (16/19 patients <

12yrs)

Follow-up occurred at

3 weeks, 6 weeks, 3

months, 6 months, and

1 year

4 patients withdrew (2

51


Characteristics


Treatment

Adverse

Effects

Monitored


Baseline: BP,

CBC,

chemistry

panel, CPK,

EPS, LFTs,

temperature

3 month

follow-up: BP,

CBC,

chemistry

panel, CPK,

EPS, LFTs,

temperature

over 6 weeks, 4.2kg over 3

months, 9.7kg over 6 months,

and 12.8kg over 1 year)

after 6 weeks and 2

after 3 months) due to

weight gain

EPS monitored using

the AIMs, Barnes

Akathisia Scale, and

Simpson Angus Scale

No clinically

significant changes

from baseline to 3

months in lab values

Kemner

(2002)

Evaluate the

efficacy of

olanzapine for

symptoms of

pervasive

developmental

disorder

N = 25

Age: 6.4-

16.6yrs (mean:

11.22yrs)

M:F = not

reported

Mean: 10.7mg/day

Range: 2.5-20mg/day

dose titration:

all patients: 2.5mg

daily or every other

day

<55kg: ↑every other

week by 2.5mg/day

max = 15mg/day

>55kg: ↑every other

week by 5mg/day

max = 20mg/day


clinical

chemistry,

ECG,

electrolytes,

hematology,

LFTs, physical

exam, pulse,

temperature,

urinalysis,

weight

Bi-weekly:

adverse

effects, BP,

EPS, pulse,

temperature,

weight

Akathisia: 1/25 (3/25 with

questionable akathisia)

↑ Appetite: 14/25

Asthenia: 14/25


EPS: 3/25

Nervousness: 6/25

QTc prolongation: 0/25

Salivation: 4/25

Somnolence: 6/25

Adverse effects

monitored via

observation and

questioning of patients

EPS monitored using

the Barnes Akathisia

Scale, and Simpson

Angus Scale

2 patients withdrew

(no explanation

provided for 1 patient,

parents unsatisfied

with procedure for

other patient)

EPS resolved in all 3

patients after dose

52


Characteristics


Treatment

Adverse

Effects

Monitored


ECG repeated

3 times

Lab tests

repeated 1-2

times

Tremor: 5/25

Weight gain: 14/25 (mean ↑

of 5.8kg)

lowered

All lab tests within the

normal range

Frazier

(2001)

Evaluate the

efficacy and

tolerability of

olanzapine for

the treatment of

acute mania in

children and

adolescents

N = 23

Age: 5.4-

14.7yrs (mean:

10.3±2.9yrs)

M:F = 13:10

Mean:

9.6±4.3mg/day

Mean mg/kg dose:

0.21±0.1mg/kg/day

Range: 2.5-20mg/day


daily, then ↑ in

2.5mg increments

every 3 days

(depending on

patient response and

adverse effects)

max = 20mg/day

8 weeks Baseline:

ECG, EPS,

hematology,

LFTs, physical

exam,

prolactin,

urinalysis

Weekly: BP,

EPS, height,

pulse, weight

Bi-weekly:

Hematology,

LFTs,

prolactin

(week 2 only)

urinalysis

Study

completion

(week 8): BP,

ECG, height,

hematology,

LFTs, physical

exam,

prolactin,

Abdominal pain: 7/23

Akathisia: 2/23

↑ ALT (above normal limits):

2/23

↑ Appetite: 14/23

BG abnormalities: 0/23

↑ BMI: 7/23

↑ Cholesterol: 1/23

Depression: 6/23

Diarrhea: 5/23

EPS: 0/23

Fever: 5/23

↑ Heart rate: proportion of


11.3±14.9bpm)

EPS monitored using

the AIMs, Barnes

Akathisia Scale, and

Simpson Angus Scale

1 patient withdrew at

week 6 due to ↑

depressive symptoms

and suicidal ideation

3 patients considered

obese at trial

completion based on

BMI (none at

beginning of the study)

No clinical

signs/symptoms

associated with

prolactin ↑

No clinically

significant changes in

hematology parameters

53


Characteristics


Treatment

Adverse

Effects

Monitored


pulse,

urinalysis

weight Infection: 5/23

↑Prolactin (above normal

limits): 6/21



9.8±14.5bpm)

Somnolence: 10/23


5±2.3kg)

Malone

(2001)

Obtain pilot data

on safety, dosing

and effectiveness

of olanzapine

compared to

haloperidol in

children with

autistic disorder

G1

(olanzapine):

N = 6

Age: 4.9-

11.8yrs (mean:

8.5±2.4yrs)

M:F = 4:2

G2

(haloperidol):

N = 6

Age: 4.9-

11.8yrs (mean:

7.3±1.9yrs)

M:F = 4:2

Mean:

7.9±2.5mg/day

Range: 5-10mg/day

doses titration:

<40kg: 2.5mg every

other day

>40kg: 2.5mg daily

doses in both weight

groups ↑ in 2.5mg

increments up to

5mg/week

max = 20mg/day


CBC, ECG,

LFTs, height,

pulse, weight

Weekly:

adverse

effects, BP,

weight

Study

completion:

adverse

effects, BP,

CBC, ECG,

LFTs, height,

pulse, weight

G1:

Ataxia: 0/6

Behavioural toxicity: 0/6

Drowsiness: 5/6

Dry mouth: 1/6

Enuresis: 1/6

EPS: 0/6

Insomnia: 1/6

Nausea/vomiting: 2/6


Adverse effects

monitored using the

Dosage Record and

Treatment Emergent

Symptom Scale and

Treatment Emergent

Symptom Scale Write-

In

EPS monitored using

the AIMs, and

neurologic rating scale

No clinically

significant differences

in any lab values

measured

54


Characteristics


Treatment

Adverse

Effects

Monitored


Rash: 0/6

Rigidity: 0/6

Tachycardia: 0/6


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


Rash: 1/6

Rigidity: 1/6

55


Characteristics


Treatment

Adverse

Effects

Monitored


Tachycardia: 1/6


1.5±2.2kg, range: -2.5-4kg)

Weight loss: 1/6

Sholevar

(2000)

Report clinical

observations of

youth with

childhood-onset

schizophrenia

treated with

olanzapine

N = 15

Age: 6-13yrs

(mean:

9.4±1.99yrs)

M:F = 9:6

Mean: 4.8mg/day

Range: 2.5-5mg/day

dose titration: 1st 3

patients: 5mg daily,

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

Mean: 11.3

days

Twice daily:

adverse

effects, BP,

pulse,

respiration,

and sedation

Sedation: 11/15

Weight gain: 0/15

No significant

autonomic or

hemodynamic adverse

effects observed

Retrospective Reviews


Characteristics


Treatment

Adverse

Effects

Monitored


Turkel

(2013)

Describe the

response to

antipsychotic

medication in

N = 16

Age: 7-34mths

(mean:

20.5±8mths)

Mean:

4.81±5.76mg/day

Range: 0.5-23mg/day

Mean:

39±41.4

days

Not reported Cardiac arrhythmia: 0 /16

EPS: 0/16

3/16 patients died of

their underlying

condition

56


Characteristics


Treatment

Adverse

Effects

Monitored


infants and

toddlers

experiencing

delirium

M:F = not

reported dose titration: 0.125-

1.25mg qhs or bid, ↑

based on efficacy

Range: 2-

151 days

Turkel

(2012)

Describe the use

of atypical

antipsychotics in

controlling

symptoms of

delirium in

children and

adolescents

N = 78

Age: 1-18yrs

(mean:

10.8±4.9yrs)

M:F = not

reported

Mean: 10mg/day

Range: 0.625-

60mg/day

Mean: 26.5

days

Range: 1-

132 days)

Adverse

effects

obtained from

patients’

medical

records

Arrhythmia: 0/78

Dystonia: 1/78

Metabolic syndrome: 0/78

Dystonia resolved with

↓ dose of olanzapine

1 patient died due to

their underlying

medical condition

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

57

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

Adverse Effect Number

of studies

Number of

children

evaluated

Mean Percentage

with Adverse

Effect

95% Confidence

Interval

Blood Glucose Abnormalities

54,58,62

3 43 4 1 to 17

Electrocardiogram Abnormalities

49,55,56,58,65

5 64 14 7 to 26

Extrapyramidal Symptoms

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

12 180 9 4 to 21

Liver Function Test Abnormalities

49,54,60

3 45 7 2 to 20

Sedation

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

12 191 48 35 to 67

Weight Gain

51,54-57,60,64

7 96 78 63 to 95

*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.

58

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

or Reporting Adverse Effect

Total Number of

Patients Evaluated

% Reported

Incidence

Akathisia

54,55,59,65

4 70 9 (6/70)

Anxiety

52,65,66

3 42 2 (1/42)

Cold/flu-like symptoms

51,52,66

3 38 29 (11/38)

Constipation

49,51,65

3 29 24 (7/29)

Dry eyes/nose/mouth

52,56,65,66

4 48 8 (4/48)

Gastrointestinal problems

52,54,56,66

4 61 25 (15/61)

Headache

51,52,65,66

[17, 19, 25, 26]

4 48 25 (12/48)

Hypersalivation

49,52,55

3 53 15 (8/53)

Urinary adverse effects

49,52,56,66

4 51 8 (4/51)

*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.

59

Table 2.6 Summary of Case Reports

Author Patient Characteristics Olanzapine Dose Length of

Treatment

Adverse

Effects

Monitored

Adverse Effects

Reported

Comments

Taskiran (2013)

N = 1

Age: 7.5yrs

Sex: M

Diagnosis: pervasive

developmental disorder

Titrated to 15mg

daily

2 months Not reported No sedation

Bozkurt (2010)

N = 1

Age: 11yrs

Sex: M

Diagnosis: catatonia

5mg daily Not reported Not reported Catatonia

No dystonia, tremor,

tardive dyskinesia or fever

Olanzapine unlikely cause

of catatonia based on

patient presentation

Herguner (2010)

N = 1

Age: 6yrs

Sex: M

Diagnosis: autistic disorder

2.5mg daily, ↑ to

7.5mg daily

Not reported Not reported Excessive masturbation Complete resolution of

masturbatory behaviour

after discontinuation of

olanzapine

Ferreira Maia

(2007)

N = 1

Age: 10yrs

Sex: M

Diagnosis: bipolar disorder

15mg daily Not reported Not reported No significant weight gain

Emiroglu (2006)

N = 1

Age: 8yrs

Sex: F

Diagnosis: bipolar disorder

15mg daily 6 months Not reported Did not experience any

adverse effects

Beresford (2005)

N = 1

Age: 4.25yrs

Sex: M

Diagnosis:

schizophreniform disorder

8.75mg daily, ↓

to 3.75mg daily

after 1 month

Not reported Not reported ↑ Appetite

Weight gain: 6.8kg

Dose ↓ due to significant

weight gain over 1 month

60


Treatment

Adverse

Effects

Monitored

Adverse Effects

Reported

Comments

Chungh (2005)

N = 1

Age: 12yrs

Sex: F

Diagnosis:

Bipolar disorder and mild

mental retardation

2.5mg daily 2 days Not reported Neuroleptic malignant

syndrome (↑ CPK, LDH,

elevated temperature)

Temperature ↓ to 36.5°C

when olanzapine stopped

Olanzapine 2.5mg re-

started – symptoms of

olanzapine-induced

neuroleptic malignant

syndrome returned

Courvoisie(2004)

N = 1

Age: 7yrs

Sex: M

Diagnosis:

ADHD, bipolar disorder,

and oppositional defiant

disorder

2.5mg QHS Approx. 9

months

Not reported ↑ BG: 14.4mmol/L

Urine positive for glucose

and ketones

Weight gain: 7.8kg (over

1 year)

Detection of ketones in

the urine may have been a

false positive secondary to

use of valproic acid

Ercan (2004)

N = 1

Age: 12yrs

Sex: M

Diagnosis: schizophrenia

5-15mg/day Not reported ECG, EPS,

LFTs, and

weight

EPS: no change in ESRS

score

Mild sedation

Weight gain: 6kg (over 26

weeks)

No clinically significant

changes in ECG or LFTs

EPS monitored using the

Extrapyramidal Symptom

Rating Scale (ESRS)

Pt followed for 26 weeks

(exact treatment duration

not reported)

Boachie (2003)

N = 4

Age: 10-12yrs (mean:

11yrs)

M:F = 1:3

Diagnosis: anorexia

nervosa

2.5mg daily Not reported Not reported Weight gain: 4/4

(≈1-1.2kg per week)

Weight gain was goal

No adverse effects

reported

61


Treatment

Adverse

Effects

Monitored

Adverse Effects

Reported

Comments

Sheikh (2002)

N = 1

Age: 10yrs

Sex: F

Diagnosis: acute agitation

and history of ADHD

Range: 2.5-

7.5mg/day

Max total daily

dose = 10mg

15 days Not reported ↑ Appetite

Weight gain: 3.2kg (over

15 days)

Mehler (2001)

N = 1

Age: 12yrs

Sex: F

Diagnosis: anorexia

nervosa

5mg daily Not reported Not reported Weight gain: 4.6kg (over

7 weeks)

Weight gain was goal

No adverse effects

reported

Nguyen (2001)

N = 1

Age: 10yrs

Sex: M

Diagnosis: ADHD

5mg daily Several months

(specific time

frame not

reported)

Not reported ↑ Total cholesterol:

5mmol/L

↑ Triglycerides:

2.06mmol/L

Weight gain: 9kg (over

several months)

Five weeks after stopping

olanzapine:

- patient lost 9kg

- total cholesterol:

3.9mmol/L (151mg/dL), -

triglycerides: 0.7mmol/L

(61mg/dL)

Bengi Semerci

(2000)

N = 1

Age: 9yrs

Sex: M

Diagnosis: Tourette’s

disorder

5mg daily, ↑ to

10mg daily

Not reported Not reported ↑ Appetite

Chang (2000)

N = 3

Age: 9-12yrs (mean:

10.3yrs)

Sex: M

Diagnosis: acute mania

Range: 2.5-5mg

daily

1-3months Not reported Sedation: 2/3

Weight gain: 2/3 (Range:

4.5-8kg)

Sedation resolved after 3

days in 1 patient, mild

daytime sedation persisted

in other patient.

Olanzapine stopped in 1

patient due to weight gain.

62


Treatment

Adverse

Effects

Monitored

Adverse Effects

Reported

Comments

Lavid (1999)

N = 2

Age: 9-10yrs (mean:

9.5yrs)

Sex: M

Diagnosis:

stuttering

Range: 1.25-

2.5mg daily

2-5mths Not reported Sedation: 0/2

Weight gain: 0/2

No adverse effects

reported for either pt

Krishnamoorthy

(1998)

N = 5

Age: 6-11yrs (mean:

9.2yrs)

M:F = 2:3

Diagnosis: psychiatric

disorder

Mean: 7.5mg/day

Mean mg/kg

dose:

0.22mg/kg/day

Range: 2.5-

10mg/day

14-52 days Not reported Akathisia: 2/5

Sedation: 2/5

Weight gain: 3/5 (↑ of 4-

8kg)

Malek-Ahmadi

(1998)

N = 1

Age: 8yrs

Sex: M

Diagnosis: hyperactivity

and aggressive behaviour

5-7.5mg daily Not reported Not reported No adverse effects

reported

Horrigan (1997)

N = 2

Age: 9-10yrs (mean:

9.5yrs)

Sex: M

Diagnosis: mental

retardation, bipolar

disorder, and autistic

behaviour

Range: 5-20mg

daily

Not reported Not reported EPS: 0/2

Mild sedation: 1/2patients

No other adverse effects

reported for either patient

ADHD = Attention Deficit Hyperactivity Disorder; CPK = creatinine phosphokinase; ECG = electrocardiogram; EPS = extrapyramidal symptoms; LDH = lactate

dehydrogenase; LFTs = liver function tests

63

Table 2.7 Summary of Overdose/Toxic Dose Articles

Author

(Year)

Patient

Characteristics

Olanzapine

Dose

Olanzapine

Level

Other Medications

Ingested

Clinical

Presentation

Onset and

Duration

of

Adverse

Effects

Abnormal

Laboratory

Values

(normal

reference

range)*

Treatment/

Follow-Up

Hail (2013)

age: 6yrs

sex: M

weight: 30kg

75-100mg

(2.5-3.3mg/kg)

Not reported Sertraline,

topiramate,

melatonin and

guanfacine

(olanzapine the only

medication taken at

a higher dose than

that prescribed)

Tachycardia,

combative,

drowsy,

agitation,

delirium

Onset: 1 hr

Duration:

48-96 hrs

K: 2.9mmol/L

(3.7-5mmol/L)

Supportive

care,

lorazepam,

diphen-

hydramine,

physostigmine,

dexmed-

etomidine,

diazepam

Tanoshima

(2013)

age: 17mths

sex: F

weight: 12.8kg

20-50mg

(1.6-3.9mg/kg)

137ng/mL

(24 hrs post-

ingestion)

None Lethargy,

drowsiness,

EPS (ataxia

and tremor)

and fever 24

hrs post-

ingestion

Onset:

unknown

(within 3.5

hrs post-

ingestion

Duration:

Fever

continued

for 3 days,

ataxia and

tremor

continued

for 5 days

Lab values

reported as

within normal

limits by

authors

Prolactin:

16.7mcg/L (on

day 2) and

13.3mcg/L (on

day 3)

(3-15mcg/L)

Activated

charcoal,

intubation,

supportive care

64

Author

(Year)

Patient

Characteristics

Olanzapine

Dose

Olanzapine

Level

Other Medications

Ingested

Clinical

Presentation

Onset and

Duration

of

Adverse

Effects

Abnormal

Laboratory

Values

(normal

reference

range)*

Treatment/

Follow-Up

Lankheet

(2011)

age: 28mths

sex: F

weight: 13kg

Reported: 30mg

(2.3mg/kg)

Estimated

based on levels:

115-230mg

(8.8-

17.7mg/kg)

888ng/mL

(approximately

6 hrs post-

ingestion

197ng/mL

(30 hrs post-

ingestion)

106ng/mL

(42 hrs post-

ingestion

None Loss of

consciousness,

slurred speech,

agitation,

tachycardia,

hypertension

then

hypotension

Onset: 6

hrs

Duration:

36 hrs

Lab values

reported as

within normal

limits by

authors

Supportive

care (oxygen,

normal saline

bolus), full

recovery

within 36 hrs

Kochhar

(2002)

age: 12yrs

sex: M

weight: not

reported

210mg

430ng/mL

(approximately

1 hr post-

ingestion)

100ng/mL

(3 days post-

ingestion)

Possibly paroxetine

and

dextroamphetamine/

amphetamine

Agitation,

combative,

miosis,

somnolence,

Onset:

approximat

ely 1 hr

post-

ingestion

Duration:

36 hrs

Lab values

reported as

within normal

limits by

authors

Charcoal,

supportive

care, no long-

term

complications

reported at 3

month follow-

up

Bond

(1999)

[61]

age: 6yrs

sex: F

weight: 17kg

10mg

(0.6mg/kg)

Not reported Possibly albuterol Slurred

speech,

staggering

gait, extreme

drowsiness,

pruritic rash,

lethargy,

ataxia, tremor

Onset:

Could not

be aroused

15 hrs

post-

ingestion

Duration:

Not reported None

65

Author

(Year)

Patient

Characteristics

Olanzapine

Dose

Olanzapine

Level

Other Medications

Ingested

Clinical

Presentation

Onset and

Duration

of

Adverse

Effects

Abnormal

Laboratory

Values

(normal

reference

range)*

Treatment/

Follow-Up

Returned

to baseline

after 7

days

Bonin

(1999)

age: 12mths

sex: M

weight: 11kg

Unknown

340ng/mL

(approximately

5 hrs post-

ingestion)

Possibly

benztropine

(undetected in urine

and serum drug

screen)

Lethargy,

“bicycling

movements of

limbs”,

irritability,

agitation,

initial

tachycardia

Onset: 1 hr

Duration:

15-16 hrs

All reported

lab values

within normal

limits

Activated

charcoal,

admitted to

Pediatric

Intensive Care

Unit for

monitoring,

discharged the

following day

without

complication

Catalano

(1999)

age: 18mths

sex: M

weight: 11kg

30-40mg

(2.7-3.6mg/kg)

213ng/mL

(4 hrs post-

ingestion)

None Somnolence,

combative,

tachycardia,

decreased

respiratory

rate

Onset: not

reported

Duration:

clinical

improveme

nt 4 hrs

post-

ingestion,

vital signs

K: 3.5mmol/L

(3.7-5mmol/L)

BUN:

8.2mmol/L

(2.9-

7.1mmol/L)

BG:

7.5mmol/L

Initially given

2 tsp syrup of

ipecac,

activated

charcoal,

gastric lavage,

intubated,

discharged the

following day

in stable

66

Author

(Year)

Patient

Characteristics

Olanzapine

Dose

Olanzapine

Level

Other Medications

Ingested

Clinical

Presentation

Onset and

Duration

of

Adverse

Effects

Abnormal

Laboratory

Values

(normal

reference

range)*

Treatment/

Follow-Up

normalized

in one day

(2.5-5mmol/L) condition

Chambers

(1998)

age: 9yrs

sex: M

weight: 29kg

100mg

(3.4mg/kg)

Not reported Acetaminophen

(unknown amount)

Combative,

tachycardia,

hypotension,

decreased

gastrointestina

l motility, EPS

Onset: 2

hrs (EPS

developed

36 hrs

post-

ingestion)

Duration:

36 hrs – 13

days

(presenting

symptoms

resolved

within 36

hrs and

EPS

continued

for 13

days)

AST: 93 (≤45)

ALT: 47 (≤40)

Activated

charcoal, N-

acetyl cysteine,

norepinephrine

, cisapride +

ondansetron +

metoclopramid

e (for

promotility

effects),

diphenhydrami

ne (for EPS)

Yip (1998)

age: 2.5yrs

sex: M

weight: 13.5kg

7.5-15mg

(0.6-1.1mg/kg)

11ng/mL

(10 hrs post-

ingestion)

None Somnolence,

agitation,

irritability,

hostility,

tachycardia,

Onset: 1 hr

Duration:

24 hrs

Lab values

reported as

within normal

limits by

authors

Monitored and

improved to

normal within

24 hrs

67

Author

(Year)

Patient

Characteristics

Olanzapine

Dose

Olanzapine

Level

Other Medications

Ingested

Clinical

Presentation

Onset and

Duration

of

Adverse

Effects

Abnormal

Laboratory

Values

(normal

reference

range)*

Treatment/

Follow-Up

miosis, hyper-

salivation,

ataxia

*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

68

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.

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 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.

69

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

72

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

75

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.

77

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.

79

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

Neuroblastoma

Other sarcomas

Brain tumors

Acute lymphoblastic leukemia

Rhabdomyosarcoma

Othera

16 (27)

12 (20)

8 (13)

7 (12)

6 (10)

6 (10)

5 (8)

Median actual body weight at beginning of each chemotherapy

block (kg; range)

44.6 (12.2 to 89.1)

Median patient age at beginning of each chemotherapy block

(years; range)

13.2 (3.10 to 17.96)

Median time from cancer diagnosis at time of administration of

first chemotherapy block during which olanzapine was given

(months; range)

3.2 (0.1 to 90.9)

aHodgkin Lymphoma, Non-Hodgkin Lymphoma, Rosai Dorfman disease, germ cell tumor

80

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

Moderate

Low

Minimal

128 (81)

28 (18)

2 (1)

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

Dexamethasone

Aprepitant

Nabilone or dronabinol

Lorazepam

Scopolamine

Promethazine

Diphenhydramine

154 (97)

90 (57)

26 (16)

21 (13)

15 (9)

7 (4)

4 (3)

2 (1)

Antiemetic agents given on an as needed basis (number of blocks; %)

Lorazepam

Hydroxyzine

Dimenhydrinate

Ondansetron or granisetron

Promethazine

Diphenhydramine

Dronabinol or nabilone

103 (65)

65 (41)

14 (9)

15 (9)

8 (5)

4 (3)

4 (3)

a One patient received daily oral temozolomide for 42 days.

81

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

Unknown

Uncontrolled CINV in current chemotherapy block

94 (59)

37 (23)

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

Twice daily

151 (96)

7 (4)

Mean initial single olanzapine dose ± standard deviation (range)

mg/kg/dose

mg/m2/dose

0.10 ± 0.051

(0.026 to 0.256)

3.0 ± 1.45

(0.81 to 6.42)

82

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

Partial CIV control

Uncontrolled CIV

Moderately emetogenic chemotherapy (20 chemotherapy blocks)


Partial CIV control

Uncontrolled CIV

Low emetic risk chemotherapy (2 chemotherapy blocks)


Partial CIV control

Uncontrolled CINV

72 (68)

23 (22)

11 (10)

9 (45)

3 (15)

8 (40)

2 (100)

0

0

Reported adverse events (number of blocks; %)

Sedation

Increased transaminase concentrationsb

Dizziness

Hiccups

Constipation

Excessive hunger

Fainting

Hypertension

Hyperglycemia

Increased plasma creatinine concentration

Stomach pain

11 (7)

5 (20)

2 (1)

2 (1)

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

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

83

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.

85

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.

88

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.

91

92

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Explorations of the use of Olanzapine for Management of … · 2015. 11. 29. · 1.1 Chemotherapy-induced Nausea and Vomiting Chemotherapy-induced nausea and vomiting (CINV) is one