explorations of the use of olanzapine for management of … · 2015. 11. 29. · 1.1...
TRANSCRIPT
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)")
6. limit 5 to English language
7. 4 or 6
Embase Classic+Embase 1947 to 2013 Week 39
1. olanzapine/
2. limit 1 to (infant <to one year> or child <unspecified age> or preschool child <1 to 6 years>
or school child <7 to 12 years>
3. limit 2 to English language
4. (Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or
"ly170053" or meltolan or midax or olace or oladay or olan or olandus or olanex or olansek or
olapin or olazax or oleanz or olexar or oltal or olzap or onza or "ozapin md" or psychozap or
relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav).tw.
5. (infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or
pediatric*).mp.
6. 4 and 5
7. limit 6 to English language
8. 3 or 7
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
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
Web of Science
Science Citation Index Expanded (SCI-EXPANDED) --1900-present
Social Sciences Citation Index (SSCI) --1956-present
Conference Proceedings Citation Index- Science (CPCI-S) --1990-present
Conference Proceedings Citation Index- Social Science & Humanities (CPCI-SSH)-1990-present
# 4 #2 AND #1
Refined by: Languages=( ENGLISH )
Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years
# 3 #2 AND #1
Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years
# 2 TS=(infan* or neonat* or child* or girl* or boy* or tot or tots or toddler* or paediatric* or
pediatric*)
Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years
# 1 TS=(Olanzapine or anzatric or "dopin tab" or "jolyon md" or lanopin or lanzac or "ly 170053" or
"ly170053" or meltolan or midax or olace or oladay or olan or olandus or olanex or olansek or
olapin or olazax or oleanz or olexar or oltal or olzap or onza or "ozapin md" or psychozap or
relprevv or zalasta or zelta or zydis or zypadhera or zyprex or zyprexa or zyprexav)
Databases=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=All years
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
Moderate 40 12.2±2.2yrs
(7-17yrs)
Autism
7.5mg/day
(5-10mg/day)
13 weeks
McCracken 2008 Prospective,
open-label
Moderate 12 11.33±2.35yrs
(7-14yrs)
Tourette syndrome
11.3±5.6mg/day
(2.5-20mg/day)
6 weeks
Quintana 2007 Prospective,
open-label
Moderate 16 12.9±2.48yrs
(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
Moderate 10 12.6±2.02yrs
(10-15yrs)
Asperger disorder
8.25mg/day
(5-15mg/day)
12 weeks
29
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
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
Moderate 10 9.9±1.7yrs
(7-13yrs)
Tourette syndrome
14.5mg/day
(1.25-20mg/day)
8 weeks
Mozes 2003 Prospective,
open-label
Moderate 9 12.5±1.13yrs
(11-14yrs)
Childhood-onset
schizophrenia
15.56±4.64mg/day
(10-20mg/day)
10 weeks
Ross 2003 Prospective,
open-label
Moderate 19 10.5±2.4yrs
(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
Moderate 23 10.3±2.9yrs
(5.4-14.7yrs)
Acute mania
9.6±4.3mg/day
(2.5-20mg/day)
8 weeks
30
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
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
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
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
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
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)
N/A 1 2.3yrs Not applicable
Reported: 30mg
Estimated based on
levels: 115-230mg Not applicable
Kochhar 2002 Case report
(overdose)
N/A 1 12yrs Not applicable
210mg
Not applicable
33
N: Number, N/A: not applicable, RCT: Randomized-controlled trial
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
Bond 1999 Case report
(overdose)
N/A 1 6yrs Not applicable
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)
N/A 1 1.5yrs Not applicable
30-40mg
Not applicable
Chambers 1998 Case report
(overdose)
N/A 1 9yrs Not applicable
100mg
Not applicable
Yip 1998 Case report
(overdose)
N/A 1 2.5yrs Not applicable
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
↑ Appetite: 4/12
↑ BMI: proportion of patients
not reported (mean: 1.6±2.5)
Constipation: 2/12
Difficulty Concentrating:
4/12
ECG abnormalities: 2/12
Enuresis: 5/12
Hypercholesterolemia: 1/12
(mean cholesterol level:
6.8mmol/L)
Hypersalivation: 8/12
Hypertension: 7/11
Hypertriglyceridemia: 1/12
(mean triglyceride level:
5.3mmol/L)
Insomnia: 3/12
LFT abnormalities: 0/12
Somnolence: 3/12
38
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Tachycardia (>100bpm): 8/10
Weight gain: proportion of
patients not reported
(mean: 3.8±6kg)
Prospective single-blind/open-label/naturalistic studies
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
8 weeks Baseline: BP,
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
prolactin, and
weight
GI problems: 5/17
↑ BG: proportion of patients
not reported (mean:
1.08mmol/L)
↑ HDL: proportion of patients
not reported (mean:
0.14mmol/L)
Headache: 4/17
Neurological adverse effects
(spacey, tremor, akathisia,
dazed, nystagmus, speech
deterioration): 3/17
↑ Pulse: proportion of
patients not reported (mean:
10.8bpm)
↑ Prolactin: proportion of
patients not reported (mean:
4.7ng/dL)
Sedation: 7/17
Sleep problems: 0/17
Skin Disturbance:1/17
Tics: 1/17
Urinary adverse effects: 0/17
40
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Weight gain: proportion of
patients not reported (mean:
5.3±2.1kg)
G2:
Aches & Pains: 3/23
Agitation/activation: 3/23
Anxiety: 0/23
↑ Appetite: 10/23
↑ Cholesterol: proportion of
patients not reported (mean:
0.63mmol/L)
Cold/flu/allergies/infection:
4/23
Depression: 1/23
Dry eyes, nose, or mouth:
0/23
GI problems: 3/23
↑ HDL: proportion of patients
not reported (mean:
0.2mmol/L)
41
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Headache: 3/23
↑ LDL: proportion of patients
not reported (mean:
0.31mmol/L)
Neurological adverse effects
(spacey, tremor, akathisia,
dazed, nystagmus, speech
deterioration): 1/23
↑ Pulse: proportion of
patients not reported (mean:
16.9bpm)
Sedation: 3/23
Sleep problems: 1/23
Skin Disturbance: 1/23
Tics: 0/23
↑ Triglycerides: proportion of
patients not reported (mean:
0.76mmol/L)
Urinary adverse effects: 3/23
Weight gain: proportion of
patients not reported (mean:
2.6±3.6kg)
42
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
dose titration: 2.5mg
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
LFT abnormalities: 0/40
Weight gain: proportion of
patients not reported (mean:
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
↑ Pulse: proportion of
patients not reported (mean:
13bpm)
Weight gain: 12/12 (mean:
4kg, range: 1.1-7.7kg)
Adverse effects
spontaneously reported
and monitored weekly
by physical
examination
Sedation and increased
appetite frequently
reported
43
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
dose titration: 2.5mg
daily, then ↑ (or ↓) in
increments of 2.5mg
ever 4-8 days
max = 20mg/day
9 weeks Baseline: BP,
CBC,
chemistry
profile, EPS,
HCG (if of
childbearing
potential),
pulse,
urinalysis,
weight
Weekly:
adverse
effects, BP,
EPS, pulse,
weight
Study
EPS: 3/16
Weight gain: proportion of
patients not reported (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
dose titration: 2.5mg
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
ECG abnormalities: 2/10
(not thought to be from
olanzapine)
EPS: 0/10
Weight gain: proportion of
patients not reported (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
dose titration: 2.5mg
daily, then ↑ based
on clinical response
and adverse effects
max = 20mg/day
12 weeks Baseline: BP,
pulse, weight
Weekly: BP,
EPS, pulse,
weight
Study
completion:
BP, EPS,
pulse, weight
G1:
Akathisia: 3/12
EPS: 7/12
Weight gain: proportion of
patients not reported (mean:
5.78±3.1kg)
G2:
Akathisia: 1/13
EPS: 8/13
Weight gain: proportion of
patients not reported (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
Agitation/activation: 1/15
Anxiety: 0/15
↑ Appetite: 9/15
Cardiovascular adverse
effects: 0/15
Cold/flu/allergies/infection:
6/15
Drooling: 0/15
Dry eyes, nose, or mouth:
1/15
Adverse effects
spontaneously reported
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
GI problems: 1/15
Headache: 2/15
Neurological adverse effects:
1/15
↑ Prolactin: proportion of
patients not reported (mean:
11.9ng/dL)
↑ Pulse: proportion of
patients not reported (mean:
17bpm)
Respiratory adverse effects:
0/15
Sedation: 3/15
Skin Disturbance:1/15
Urinary adverse effects: 2/15
Weight gain: proportion of
patients not reported (mean:
3.2±0.7kg)
G2:
Aches & Pains: 0/16
48
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Agitation/activation: 2/16
Anxiety: 1/16
↑ Appetite: 8/16
↑ BP (systolic): proportion of
patients not reported (mean:
9.8)
Cardiovascular adverse
effects: 1/16
Cold/flu/allergies/infection:
5/16
Drooling: 1/16
Dry eyes, nose, or mouth:
3/16
GI problems: 4/16
Headache: 5/16
Neurological adverse effects:
0/16
↑ Prolactin: proportion of
patients not reported (mean:
35.7ng/dL)
Respiratory adverse effects:
2/16
49
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Sedation: 4/16
Skin Disturbance:0/16
Urinary adverse effects: 1/16
Weight gain: proportion of
patients not reported (mean:
2.2±0.4kg)
Stephens
(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
dose titration: 2.5mg
daily for 2 weeks,
then ↑ to 5mg daily
for 2 weeks (if
tolerated), then ↑in
5mg increments bi-
weekly as tolerated
max = 20mg/day
8 weeks Baseline: BP,
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
ECG abnormalities: 0/10
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
chemistry,
ECG,
hematology,
height, pulse,
weight
Headache: 5/10
Psychomotor slowing: 0/10
Weight gain: proportion of
patients not reported (mean:
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
dose titration: 2.5mg
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
ECG abnormalities: 0/9
EPS: 0/9
↑LFTs: 0/9
Somnolence: 7/9
Weight gain: 9/9 (mean:
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
Weight gain: proportion of
patients not reported (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
12 weeks Baseline: BP,
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
ECG abnormalities: 4/25
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
dose titration: 2.5mg
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
patients not reported (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
pulse,
urinalysis
weight Infection: 5/23
↑Prolactin (above normal
limits): 6/21
↑ Pulse: proportion of
patients not reported (mean:
9.8±14.5bpm)
Somnolence: 10/23
Weight gain: 7/23 (mean:
5±2.3kg)
Malone
(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
6 weeks Baseline: BP,
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
QTc prolongation: 0/6
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Rash: 0/6
Rigidity: 0/6
Tachycardia: 0/6
Weight gain: 6/6 (mean:
4.1±1.6kg, range: 2.7-7.1kg)
G2:
Ataxia: 1/6
Behavioural toxicity: 2/6
Drowsiness: 2/6
Dry mouth: 1/6
Enuresis: 1/6
EPS: 0/6
Insomnia: 0/6
Nausea/vomiting: 0/6
QTc prolongation: 0/6
Rash: 1/6
Rigidity: 1/6
55
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
Tachycardia: 1/6
Weight gain: 5/6 (mean:
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
Author Study Aim Patient
Characteristics
Olanzapine Dose Length of
Treatment
Adverse
Effects
Monitored
Adverse Effects Reported Comments
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
Author Patient Characteristics Olanzapine Dose Length of
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
Author Patient Characteristics Olanzapine Dose Length of
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
Author Patient Characteristics Olanzapine Dose Length of
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)
Complete CIV control
Partial CIV control
Uncontrolled CIV
Low emetic risk chemotherapy (2 chemotherapy blocks)
Complete CIV control
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
References
1. Cohen L, de Moor CA, Eisenberg P, Ming EE, Hu H. Chemotherapy-induced nausea and
vomiting: incidence and impact on patient quality of life at community oncology settings.
Support Care Cancer 2007;15:497-503.
2. Dupuis LL, Milne-Wren C, Cassidy M, et al. Symptom assessment in children receiving
cancer therapy: the parents' perspective. Support Care Cancer 2010;18:281-99.
3. Fernandez-Ortega P, Caloto MT, Chirveches E, et al. Chemotherapy-induced nausea and
vomiting in clinical practice: impact on patients' quality of life. Support Care Cancer
2012;20:3141-8.
4. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer journal (Sudbury, Mass)
2008;14:85-93.
5. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute
antiemetic control. The Oncologist 2003;8:187-98.
6. Dupuis LL, Boodhan S, Holdsworth M, et al. Guideline for the prevention of acute
nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatric
Blood & Cancer 2013;60:1073-82.
7. Hesketh PJ. Chemotherapy-induced nausea and vomiting. The New England journal of
medicine 2008;358:2482-94.
8. Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and
vomiting. Providing a basis for therapeutic progress. Oncology (Williston Park, NY) 2004;18:9-
14.
9. Dupuis L, Boodhan S, Sung L, et al. Guideline for the classification of the acute
emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood
Cancer 2011;57:191-8.
10. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute
emetogenicity of cancer chemotherapy. Journal of clinical oncology : official journal of the
American Society of Clinical Oncology 1997;15:103-9.
11. Hesketh PJ, Gralla RJ, du Bois A, Tonato M. Methodology of antiemetic trials: response
assessment, evaluation of new agents and definition of chemotherapy emetogenicity. Support
Care Cancer 1998;6:221-7.
12. Warr D. Prognostic factors for chemotherapy induced nausea and vomiting. European
Journal of Pharmacology 2014;722:192-6.
13. Freedman J, Faerber J, Kang T, et al. Predictors of antiemetic alteration in pediatric acute
myeloid leukemia. Pediatric Blood and Cancer 2014; 61:1798–805.
93
14. Holdsworth MT, Raisch DW, Frost J. Acute and delayed nausea and emesis control in
pediatric oncology patients. Cancer 2006;106:931-40.
15. Dupuis LL, Robinson PD, Boodhan S, et al. Guideline for the prevention and treatment of
anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. Pediatr Blood
Cancer 2014;61:1506-12.
16. Hesketh PJ, Aapro M, Street JC, Carides AD. Evaluation of risk factors predictive of
nausea and vomiting with current standard-of-care antiemetic treatment: analysis of two phase III
trials of aprepitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer
2010;18:1171-7.
17. Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the
prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-
blind, phase 3 trial. The Lancet Oncology 2015;16:385-94.
18. Basch E, Prestrud A, Hesketh P, et al. Antiemetics: American Society of Clinical
Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology 2011;29:4189-98.
19. Eli Lilly and Company. Zyprexa Prescribing Information. Indianapolis: Eli Lilly and Co.;
2010.
20. Shahid M, Walker GB, Zorn SH, Wong EH. Asenapine: a novel psychopharmacologic
agent with a unique human receptor signature. J Psychopharmacol 2009;23:65-73.
21. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from
receptor-binding profiles. Molecular psychiatry 2008;13:27-35.
22. Bever KA, Perry PJ. Olanzapine: a serotonin-dopamine-receptor antagonist for
antipsychotic therapy. American journal of health-system pharmacy : AJHP : official journal of
the American Society of Health-System Pharmacists 1998;55:1003-16.
23. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and
pharmacodynamic profile. Clinical pharmacokinetics 1999;37:177-93.
24. Sheehan JJ, Sliwa JK, Amatniek JC, Grinspan A, Canuso CM. Atypical Antipsychotic
Metabolism and Excretion. Current Drug Metabolism 2010;11:516-25.
25. Grothe DR, Calis KA, Jacobsen L, et al. Olanzapine pharmacokinetics in pediatric and
adolescent inpatients with childhood-onset schizophrenia. J Clin Psychopharmacol 2000;20:220-
5.
26. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the
atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:87-96.
27. Hocking CM, Kichenadasse G. Olanzapine for chemotherapy-induced nausea and
vomiting: a systematic review. Support Care Cancer 2014;22:1143-51.
94
28. Navari R, Einhorn L, Passik S, et al. A phase II trial of olanzapine for the prevention of
chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Supp Care
Cancer 2005;13:529-34.
29. Navari RM, Einhorn LH, Loehrer PJ, Sr., et al. A phase II trial of olanzapine,
dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and
vomiting: a Hoosier oncology group study. Support Care Cancer 2007;15:1285-91.
30. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of
chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol
2011;9:188-95.
31. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the
treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving
highly emetogenic chemotherapy. Support Care Cancer 2013;21:1655-63.
32. Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of
chemotherapy-induced nausea and vomiting. Journal of Experimental & Clinical Cancer
Research 2009;28:131-7.
33. Wang XF, Feng Y, Chen Y, Gao BL, Han BH. A meta-analysis of olanzapine for the
prevention of chemotherapy-induced nausea and vomiting. Scientific reports 2014;4:4813.
34. Passik SD, Kirsh KL, Theobald DE, et al. A retrospective chart review of the use of
olanzapine for the prevention of delayed emesis in cancer patients. Journal of Pain & Symptom
Management 2003;25:485-8.
35. Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of
olanzapine for the relief of nausea in patients with advanced cancer and pain. Journal of Pain &
Symptom Management 2002;23:526-32.
36. Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) for the
prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer
Investigation 2004;22:383-8.
37. MASCC/ESMO Antiemetic Guideline 2013. 2013. (Accessed May, 2015, at
http://www.mascc.org/assets/documents/mascc_guidelines_english_2013.pdf.)
38. National Comprehensive Cancer Network. Antiemesis 1.2014. National Comprehensive
Cancer Network; 2014.
39. Gopalakrishnan S, Ganeshkumar P. Systematic reviews and meta-analysis: understanding
the best evidence in primary healthcare. Journal of Family Medicine and Primary Care 2013;2:9-
14.
40. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic
reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and
elaboration2009.
95
41. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement2009.
42. Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation
antipsychotic medications in children and adolescents. Journal of Child & Adolescent
Psychopharmacology 2004;14:372-94.
43. Masi G. Pharmacotherapy of pervasive developmental disorders in children and
adolescents. CNS Drugs 2004;18:1031-52.
44. Olfson M, Crystal S, Huang C, Gerhard T. Trends in antipsychotic drug use by very
young, privately insured children. Journal of the American Academy of Child & Adolescent
Psychiatry 2010;49:13-23.
45. Pfeifer J, Kowatch R, DelBello M. Pharmacotherapy of bipolar disorder in children and
adolescents. Recent progress. CNS Drugs 2010;24:576-93.
46. Almandil NB, Liu Y, Murray ML, Besag FMC, Aitchison KJ, Wong ICK. Weight gain
and other metabolic adverse effects associated with atypical antipsychotic treatment of children
and adolescents: a systematic review and meta-analysis. Paediatric drugs 2013;15:139-50.
47. Cohen D, Bonnot O, Bodeau N, Consoli A, Laurent C. Adverse effects of second-
generation antipsychotics in children and adolescents: a Bayesian meta-analysis. J Clin
Psychopharmacol 2012;32:309-16.
48. Norris ML, Spettigue W, Buchholz A, et al. Olanzapine use for the adjunctive treatment
of adolescents with anorexia nervosa. Journal of Child & Adolescent Psychopharmacology
2011;21:213-20.
49. Shaw P, Sporn A, Gogtay N, et al. Childhood-onset schizophrenia: A double-blind,
randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006;63:721-30.
50. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in
studies of prognostic factors. Annals of Internal Medicine 2013;158:280-6.
51. Hollander E, Wasserman S, Swanson EN, et al. A double-blind placebo-controlled pilot
study of olanzapine in childhood/adolescent pervasive developmental disorder. Journal of Child
& Adolescent Psychopharmacology 2006;16:541-8.
52. Biederman J, Mick E, Hammerness P, et al. Open-label, 8-week trial of olanzapine and
risperidone for the treatment of bipolar disorder in preschool-age children. Biol Psychiatry
2005;58:589-94.
53. Fido A, Al-Saad S. Olanzapine in the treatment of behavioral problems associated with
autism: an open-label trial in Kuwait. Med Princ Pract 2008;17:415-8.
54. Frazier JA, Biederman J, Tohen M, et al. A prospective open-label treatment trial of
olanzapine monotherapy in children and adolescents with bipolar disorder. Journal of Child &
Adolescent Psychopharmacology 2001;11:239-50.
96
55. Kemner C, Willemsen-Swinkels SHN, de Jonge M, Tuynman-Qua H, van Engeland H.
Open-label study of olanzapine in children with pervasive developmental disorder. J Clin
Psychopharmacol 2002;22:455-60.
56. Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA. Olanzapine versus
haloperidol in children with autistic disorder: an open pilot study. Journal of the American
Academy of Child & Adolescent Psychiatry 2001;40:887-94.
57. McCracken JT, Suddath R, Chang S, Thakur S, Piacentini J. Effectiveness and
tolerability of open label olanzapine in children and adolescents with Tourette syndrome. Journal
of Child & Adolescent Psychopharmacology 2008;18:501-8.
58. Milin R, Simeon JG, Batth S, Thatte S, Dare GJ, Walker S. An open trial of olanzapine in
children and adolescents with Asperger Disorder. J Clin Psychopharmacol 2006;26:90-2.
59. Mozes T, Ebert T, Michal S-E, Spivak B, Weizman A. An open-label randomized
comparison of olanzapine versus risperidone in the treatment of childhood-onset schizophrenia.
Journal of Child & Adolescent Psychopharmacology 2006;16:393-403.
60. Mozes T, Greenberg Y, Spivak B, Tyano S, Weizman A, Mester R. Olanzapine treatment
in chronic drug-resistant childhood-onset schizophrenia: an open-label study. Journal of Child &
Adolescent Psychopharmacology 2003;13:311-7.
61. Quintana H, Wilson MS, 2nd, Purnell W, Layman AK, Mercante D. An open-label study
of olanzapine in children and adolescents with schizophrenia. J Psychiatr Pract 2007;13:86-96.
62. Ross R, Novins D, Farley G, Adler L. A 1-year open-label trial of olanzapine in school-
age children with schizophrenia. J Child Adolesc Psychopharmacology 2003;13:301-9.
63. Sethi S, Setiya R, Lallar K. Successful treatment of Sydenham chorea with olanzapine.
Journal of Pediatric Neurology 2006;4 (3):171-4.
64. Sholevar EH, Baron DA, Hardie TL. Treatment of childhood-onset schizophrenia with
olanzapine. Journal of Child & Adolescent Psychopharmacology 2000;10:69-78.
65. Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in
children with Tourette's syndrome--a pilot study. Journal of Child & Adolescent
Psychopharmacology 2004;14:255-66.
66. Wozniak J, Mick E, Waxmonsky J, Kotarski M, Hantsoo L, Biederman J. Comparison of
open-label, 8-week trials of olanzapine monotherapy and topiramate augmentation of olanzapine
for the treatment of pediatric bipolar disorder. Journal of Child & Adolescent
Psychopharmacology 2009;19:539-45.
67. Turkel SB, Jacobson J, Munzig E, Tavare CJ. Atypical antipsychotic medications to
control symptoms of delirium in children and adolescents. Journal of Child & Adolescent
Psychopharmacology 2012;22:126-30.
97
68. Turkel SB, Jacobson JR, Tavare CJ. The diagnosis and management of delirium in
infancy. Journal of Child and Adolescent Psychopharmacology 2013;23 (5):352-6.
69. Bengi Semerci Z. Olanzapine in Tourette's disorder. Journal of the American Academy of
Child & Adolescent Psychiatry 2000;39:140.
70. Beresford C, Hepburn S, Ross RG. Schizophrenia in pre-school children: Two case
reports with longitudinal follow-up for 6 and 8 years. Clinical Child Psychology and Psychiatry
2005;10 (3):429-39.
71. Boachie A, Goldfield GS, Spettigue W. Olanzapine use as an adjunctive treatment for
hospitalized children with anorexia nervosa: case reports. Int J Eat Disord 2003;33:98-103.
72. Bozkurt H, Mukaddes NM. Catatonia in a child with autistic disorder. Turkish Journal of
Pediatrics 2010;52 (4):435-8.
73. Chang KD, Ketter TA. Mood stabilizer augmentation with olanzapine in acutely manic
children. Journal of Child & Adolescent Psychopharmacology 2000;10:45-9.
74. Chungh D-S, Kim B-N, Cho S-C. Neuroleptic malignant syndrome due to three atypical
antipsychotics in a child. J Psychopharmacol 2005;19:422-5.
75. Courvoisie HE, Cooke DW, Riddle MA. Olanzapine-induced diabetes in a seven-year-
old boy. Journal of Child & Adolescent Psychopharmacology 2004;14:612-6.
76. Emiroglu FNI, Gencer O, Ozbek A. Adjunctive olanzapine treatment in bipolar
adolescents responding insufficiently to mood stabilizers. Four case reports. Eur Child Adolesc
Psychiatry 2006;15:500-3.
77. Ercan ES, Kutlu A, Varan A, Cikoglu S, Coskunol H, Bayraktar E. Olanzapine treatment
of eight adolescent patients with psychosis. Hum 2004;19:53-6.
78. Ferreira Maia AP, Boarati MA, Kleinman A, Fu IL. Preschool Bipolar Disorder:
Brazilian children case reports. Journal of Affective Disorders 2007;104 (1-3):237-43.
79. Herguner S. Excessive masturbation associated with olanzapine in a pediatric case. Prog
Neuropsychopharmacol Biol Psychiatry 2010;34:1349-50.
80. Horrigan JP, Barnhill LJ, Courvoisie HE. Olanzapine in PDD. Journal of the American
Academy of Child & Adolescent Psychiatry 1997;36:1166-7.
81. Krishnamoorthy J, King BH. Open-label olanzapine treatment in five preadolescent
children. Journal of Child & Adolescent Psychopharmacology 1998;8:107-13.
82. Lavid N, Franklin DL, Maguire GA. Management of child and adolescent stuttering with
olanzapine: three case reports. Ann Clin Psychiatry 1999;11:233-6.
83. Malek-Ahmadi P, Simonds JF. Olanzapine for autistic disorder with hyperactivity.
Journal of the American Academy of Child & Adolescent Psychiatry 1998;37:902.
98
84. Mehler C, Wewetzer C, Schulze U, Warnke A, Theisen F, Dittmann RW. Olanzapine in
children and adolescents with chronic anorexia nervosa. A study of five cases. Eur Child Adolesc
Psychiatry 2001;10:151-7.
85. Nguyen M, Murphy T. Olanzapine and hypertriglyceridemia. Journal of the American
Academy of Child & Adolescent Psychiatry 2001;40:133.
86. Sheikh RM, Ahmed K. The efficacy of olanzapine, as needed, to treat acute agitation in
juveniles. Journal of Child & Adolescent Psychopharmacology 2002;12:71-3.
87. Taskiran S, Coffey DBJ. Unremitting impulsive aggression in a child with childhood
onset schizophrenia and pervasive development disorder-not otherwise specified: The role of
stimulants, atypical antipsychotics and mood stabilizers. Journal of Child and Adolescent
Psychopharmacology 2013;23 (5):363-6.
88. Bond GR, Thompson JD. Olanzapine pediatric overdose. Ann Emerg Med 1999;34:292-
3.
89. Bonin MM, Burkhart KK. Olanzapine overdose in a 1-year-old male. Pediatr Emerg Care
1999;15:266-7.
90. Catalano G, Cooper DS, Catalano MC, Butera AS. Olanzapine overdose in an 18-month-
old child. Journal of Child & Adolescent Psychopharmacology 1999;9:267-71.
91. Chambers RA, Caracansi A, Weiss G. Olanzapine overdose cause of acute
extrapyramidal symptoms. Am J Psychiatry 1998;155:1630-1.
92. Hail SL, Obafemi A, Kleinschmidt KC. Successful management of olanzapine-induced
anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine
in a pediatric patient. Clin Toxicol (Phila) 2013;51:162-6.
93. Kochhar S, Nwokike JN, Jankowitz B, Sholevar EH, Abed T, Baron DA. Olanzapine
overdose: a pediatric case report. Journal of Child & Adolescent Psychopharmacology
2002;12:351-3.
94. Lankheet NAG, Padberg RD, de Kluiver EM, et al. Relatively mild symptoms after an
olanzapine intoxication in a 2-year-old girl with excessively high serum levels. Journal of Child
& Adolescent Psychopharmacology 2011;21:93-5.
95. Tanoshima R, Chandranipapongse W, Colantonio D, Stefan C, Nulman I. Acute
olanzapine overdose in a toddler: A case report. Ther Drug Monit 2013.
96. Yip L, Dart RC, Graham K. Olanzapine toxicity in a toddler. Pediatrics 1998;102:1494.
97. Robertson MD, McMullin MM. Olanzapine concentrations in clinical serum and
postmortem blood specimens--when does therapeutic become toxic? J Forensic Sci 2000;45:418-
21.
99
98. Martinez-Ortega JM, Funes-Godoy S, Diaz-Atienza F, Gutierrez-Rojas L, Perez-Costillas
L, Gurpegui M. Weight gain and increase of body mass index among children and adolescents
treated with antipsychotics: A critical review. European Child and Adolescent Psychiatry
2013;22 (8):457-79.
99. Meli M, Rauber-Lüthy C, Hoffmann-Walbeck P, et al. Atypical antipsychotic poisoning
in young children: a multicentre analysis of poisons centres data. European Journal of Pediatrics
2014;173:743-50.
100. Vig S, Seibert L, Green M. Olanzapine is effective for refractory chemotherapy-induced
nausea and vomiting irrespective of chemotherapy emetogenicity. Journal of Cancer Research &
Clinical Oncology 2014;140:77-82.
101. National Institutes of Health. Common Terminology Criteria for Adverse Events
(CTCAE) Version 4.03. U.S Department of Health and Human Services; 2010.
102. Naranjo C, Busto U, Sellers E, et al. A method for estimating the probability of adverse
drug reactions. Clin Pharmacol Ther 1981;30:239-45.
103. Schwartzberg L, Szabo S, Gilmore J, et al. Likelihood of a subsequent chemotherapy-
induced nausea and vomiting (CINV) event in patients receiving low, moderately or hghly
emetogenic chemotherapy (LEC/MEC/HEC). Current Medical Research & Opinion
2011;27:837-45.
104. Flank J, Sung L, Dvorak C, Spettigue W, Dupuis LL. The safety of olanzapine in young
children: A systematic review and meta-analysis. Drug Saf 2014;37:791-804.
105. Johnson TN. The problems in scaling adult drug doses to children. Arch Dis Child
2008;93:207-11.
106. Anderson GD, Lynne AM. Optimizing pediatric dosing: a developmental pharmacologic
approach. Pharmacotherapy 2009;29:680-90.
107. Ballard C, Peterson G, Thompson A, Beggs S. Off-label use of medicines in paediatric
inpatients at an Australian teaching hospital. Journal of Paediatrics and Child Health 2013;49:38-
42.
108. Bazzano A, Mangione-Smith R, Schonlau M, Suttorp M, Brook R. Off-label prescribing
to children in the United States outpatient setting. Academic Pediatrics 2009;9:81-8.
109. Tramontina M, Heineck I, Dos Santos l. Use of non-formulary drugs in children at a
Brazilian teaching hospital: a descriptive study. Pharmacy Practice 2013;11:17-23.
110. Uppal N, Dupuis L, Parshuram C. Documentation of pediatric drug safety in
manufacturers’ product monographs. Pediatric Drugs 2008;10:193-7.
111. Ujike H, Nomura A, Morita Y, et al. Multiple genetic factors in olanzapine-induced
weight gain in schizophrenia patients: a cohort study. The Journal of Clinical Psychiatry
2008;69:1416-22.
100
112. Hawkins R, Grunberg S. Chemotherapy-induced nausea and vomiting: challenges and
opportunities for improved patient outcomes. Clinical journal of oncology nursing 2009;13:54-
64.
113. Baxter AL, Watcha MF, Baxter WV, Leong T, Wyatt MM. Development and validation
of a pictorial nausea rating scale for children. Pediatrics 2011;127:e1542-e9.
114. Dupuis LL, Taddio A, Kerr EN, Kelly A, MacKeigan L. Development and validation of a
pediatric nausea assessment tool (PeNAT) for use by children receiving antineoplastic agents.
Pharmacotherapy 2006;26:1221-31.