DATE: 01 February 2013 CONTEXT AND POLICY ISSUES

TITLE: Ondansetron for the Management of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients: A Review of the Clinical Effectiveness, Safety and Guidelines DATE: 01 February 2013 CONTEXT AND POLICY ISSUES Chemotherapy-induced nausea and vomiting (CINV) are side effects occurring in people receiving chemotherapeutic drugs for cancer treatment. 1 Nausea and vomiting are two of the most frequent and distressing side effects 1-3 that can significantly reduce the quality of life in patients 2,4 and reduce adherence to treatment. 2 CINV remains a challenge in youth as children (above the age of 5) are typically more prone to experience vomiting upon treatment. 5 The incidence of CINV is dependent on numerous factors, the most important of which being the emetogenicity of the chemotherapeutic agents used. 1,4 Nausea and vomiting can vary depending upon emetogenicity, and for some chemotherapeutic agents the incidence of CINV can approach 90% without prophylactic anti-emetic treatment. 1 CINV can be classified into three distinct clinical phases of nausea and vomiting: anticipatory, acute, and delayed. 1,2 Anticipatory phase nausea and vomiting occurs prior to receiving the first dose in a new cycle of chemotherapy and is usually in response to an adverse reaction in a previous cycle. 1 Its estimated prevalence is 20-30% in pediatric patients receiving chemotherapy. 1 The acute phase is defined as occurring within 24 hours of receiving treatment. 1 In the delayed phase, the symptoms appear anywhere after the 24 hour period up to 120 hours and usually correspond to the use of alkylating agents or platinum compounds. The incidence of CINV with these agents is around 50%. 1 Numerous classes of anti-emetic medications are available, however the current standard of practice for pediatric populations receiving moderate to highly emetogenic chemotherapy includes treatment with a 5-hydroxytryptamine 3 (5-HT 3 ) antagonist and corticosteroids. 3,5,6 Since the 5-HT 3 receptors found in the chemoreceptor trigger zone of the brain are involved in the emetic reflex, the 5-HT 3 antagonists are quite valuable in controlling emesis, 2,7 even though 30% of patients are non-responders. 7 Ondansetron, granisetron, dolasetron, tropisetron, and palonosetron are medications belonging to the 5-HT 3 antagonist class. 7 The main side effects of 5-HT 3 antagonists include headache, diarrhea, constipation, sedation/somnolence, abdominal Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

pain, and dizziness. 1,4,8 The administration of 5-HT3 antagonists has been associated with changes in electrocardiogram (ECG) readings and may be of concern in some instances. 9 The purpose of this report is to provide evidence on the clinical effectiveness, safety, and harms of ondansetron for the management of CINV in pediatric populations. It will also report on evidence-based guidelines for the use of ondansteron for CINV in pediatric populations. RESEARCH QUESTIONS 1. What is the clinical effectiveness of ondansetron for the management of chemotherapyinduced nausea and vomiting (CINV) in pediatric patients? 2. What is the clinical evidence on the safety and harms of ondansetron for the management of CINV in pediatric patients? 3. What are the evidence-based guidelines regarding the use of ondansetron for the management of CINV in pediatric patients? KEY FINDINGS For the management of CINV in the pediatric population, the antiemetic effects of ondansetron plus dexamethasone appeared to be better than ondansetron alone or placebo. There was no statistically significant difference in antiemetic effect between ondansetron and tropisetron. There were some inconsistencies in the results for antiemetic effects of ondansetron compared with granisetron. Numerical values suggested that the antiemetic effects of palonosetron was greater compared to ondansetron, however it was unclear if the differences were statistically significant. It should be noted that in most instances, for each comparison there was only one relevant study. Clinical practice guidelines recommended ondansetron as a treatment option for controlling CINV in the pediatric population. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 12), University of York Centre for Reviews and Dissemination (CRD) databases, EMBASE, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2008 and January 3, 2013. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and selected potentially relevant articles for retrieval of full-text publications for further investigation. A second reviewer evaluated the full-text publications for final selection, according to the criteria listed in Table 1. Ondansetron for the Management of CINV in Pediatric Patients 2

Table 1: Selection Criteria Population Pediatric patients ( 18 years old) undergoing chemotherapy treatment and are experiencing symptoms of nausea and/or vomiting chemotherapy-induced nausea and vomiting (CINV) Intervention Ondansetron Comparator Outcomes Study Designs Placebo Active comparators Decrease in nausea and vomiting Adverse events Guidelines and recommendations (how many tablets to administer, when to administer, patient criteria) Health technology assessments, systematic reviews and metaanalyses, randomized controlled trials (RCT), non-randomized studies and evidence-based guidelines Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria in Table 1, if they were published prior to 2008, or duplicate publications of the same study and did not provide additional relevant information. Individual studies which were included in at least one of the included systematic reviews were excluded. Systematic reviews which did not report results specifically for ondansetron were excluded. Critical Appraisal of Individual Studies Critical appraisal of a study was conducted based on an assessment tool appropriate for the particular study design. The AMSTAR checklist 10 was used for systematic reviews; the Downs and Black checklist 11 for RCTs and non-randomized studies; and the AGREE checklist 12 for guidelines. For the critical appraisal, a numeric score was not calculated. Instead, the strength and limitations of the study were described. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 226 citations. Upon screening titles and abstracts, 213 articles were excluded and 13 potentially relevant articles were selected for full-text review. Five potentially relevant articles were identified from the grey literature. Of these 18 articles, 12 did not satisfy the inclusion criteria and were excluded. Two systematic reviews, one RCT, one nonrandomized study, and two evidence-based guidelines were relevant and selected for inclusion. No relevant health technology assessment was identified. Details of the study selection process are outlined in Appendix 1. Ondansetron for the Management of CINV in Pediatric Patients 3

Summary of Study Characteristics Characteristics of the included systematic reviews, RCTs, non-randomized studies and guidelines are summarized below and details are provided in Appendices 2 and 3. Systematic reviews Two 1,13 relevant systematic reviews were included. One 1 was published in 2010 from UK and one 13 was published from USA in 2009. Both systematic reviews included studies on a variety of antiemetics, however results for studies with ondansetron were reported separately and are included here. One systematic review 1 included only RCTs and one 13 included both RCTs and non-randomized studies. One systematic review 1 included patients (<18 years) requiring antiemetics for either prevention or treatment of nausea and vomiting, associated with chemotherapy. It included 28 RCTs of which 10 compared ondansetron with an active comparator or another ondansetron dose or placebo. One systematic review 13 included children and adults requiring antiemetics for either prevention or treatment of nausea and vomiting, associated with chemotherapy of various emetogenicity, radiation therapy, surgical procedure or pregnancy. It included 34 studies of which seven studies were on children undergoing chemotherapy and compared ondansetron with an active comparator or another ondansetron dose. Both systematic reviews reported on antiemetic effects in the acute and delayed phase of CINV. There was limited reporting of adverse events. Randomized controlled study (RCT) One 2 relevant RCT was included. It was published in Bangladesh in 2011. It was a double blind, single center study comparing ondansetron with granisetron in children with acute lymphoblastic leukemia receiving chemotherapy. It included 60 patients in the age range four to 11 years. It reported on antiemetic effects, biochemical markers and adverse events. Follow up was up to four days. Non-randomized study One 3 relevant non-randomized study was included. It was published in Switzerland in 2008. It was a retrospective single center study and included patients who had received at least one ondansetron-loading dose. It included 37 patients of median age 6.9 years and age range 0.4 year to 15.7 years receiving chemotherapy for various cancers. The study reported on adverse events. Follow up was for 24 hours. Guidelines Two 6,14 evidence-based guidelines were included. One guideline 14 was published from Canada in 2012 by the Pediatric Oncology Group of Ontario. It provided guidance on the selection of interventions for the optimal control of acute CINV in pediatric cancer patients receiving chemotherapy. The recommended antiemetics were restricted to those available in Canada at the time the guideline was developed. One guideline 6 was published from the USA in 2011 and was an update of a previous American Society of Clinical Oncology Clinical Practice Guideline. This guideline update focused on antiemetics for patients receiving cancer therapy. The characteristics on the grading of recommendations and levels of evidence used to develop the guidelines are provided in Appendix 3. Ondansetron for the Management of CINV in Pediatric Patients 4

Summary of Critical Appraisal Systematic reviews Both systematic reviews 1,13 stated the inclusion/exclusion criteria, conducted a comprehensive literature search, performed article selection in duplicate, provided a list of included and excluded studies, reported on individual study characteristics, and conducted quality assessment of the included studies. In one systematic review 1 data extraction was done in duplicate and in one systematic review 13 it was unclear. Publication bias was not explored. Considering that for most comparisons there was only one study included, the assessment of publication bias or definitive conclusions are difficult. Randomized controlled trial (RCT) The included RCT 2 was double blind. Inclusion and exclusion criteria, patient characteristics, intervention and outcomes were described. However patient characteristics of the two groups were not provided separately, so it is unclear whether baseline characteristics of the intervention and comparator groups were comparable. A sample size calculation was not described. Non-randomized study The included non-randomized study 3 was a retrospective study and had no comparator group. Inclusion and exclusion criteria, patient characteristics, intervention and outcomes were described. The study design has inherent limitations. As there is no comparator, one cannot definitively attribute effects specifically to the drug. Guidelines In the two included guidelines 6,14 the scope and purpose were stated, the methodology used was rigorous and the recommendations were clear. For both guidelines, the guideline development group comprised of individuals from relevant clinical areas. It was unclear if patient input was sought. One guideline 14 mentioned organizational barriers and cost implications and one 6 did not. Strengths and limitations of individual systematic reviews and guidelines are provided in Appendix 4. Summary of Findings The overall findings are summarized below and details of the findings of included systematic reviews, RCT, and non-randomized study are provided in Appendix 5 and details of the included guidelines are provided in Appendix 6. What is the clinical effectiveness of ondansetron for the treatment of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients? Ondansetron for the Management of CINV in Pediatric Patients 5

Ondansetron versus placebo One systematic review, 1 which included one RCT comparing ondansetron with placebo, showed that complete control of vomiting in the acute phase was statistically significantly greater with ondansetron. Ondansetron versus metoclopramide with procyclidine and dexamethasone One systematic review, 1 which included one RCT comparing ondansetron with metoclopramide combined with procyclidine and dexamethasone showed that complete control of vomiting in the acute phase was statistically significantly greater with ondansetron. Ondansetron versus ondansetron (different doses or different routes of administration) One systematic review, 1 which included two RCTs comparing different doses of ondansetron, showed that during the acute phase there were no statistically significant differences in complete control of nausea, vomiting or nausea and vomiting when various ondansetron doses were compared. One RCT compared ondansetron doses of 5 mg/m 2 and 10 mg/m 2 given intravenously over 15 minutes before chemotherapy and one RCT compared ondansetron doses of 0.15 mg/kg and 0.6 mg/kg given intravenously over 30 minutes before chemotherapy. One systematic review, 13 which included one RCT comparing different routes of ondansetron administration, showed that during the acute phase and subsequent phases there were no statistically significant differences in complete control and major control of nausea between 8 mg ondansetron administered orally and 5 mg/m 2 administered intravenously. Ondansetron with dexamethasone versus ondansetron One systematic review, 1 which included one RCT comparing ondansetron plus dexamethasone with ondansetron alone, showed that complete control of vomiting in the acute phase was statistically significantly greater with ondansetron plus dexamethasone compared with ondansetron alone Ondansetron versus tropisetron One systematic review, 1 which included one RCT comparing ondansetron with tropisetron showed that during both the acute and delayed phases there were no statistically significant differences in complete control of nausea or vomiting. Ondansetron versus granisetron versus tropisetron One systematic review, 13 which included one RCT comparing ondansetron, granisetron and tropisetron, showed that there were no statistically significant differences in complete response rates, partial response rate and failure rates between the three drugs. Ondansetron versus granisetron Two systematic reviews, 1,13 included the same RCT comparing ondansetron and granisetron in the acute phase. The proportion of complete responses was numerically higher with granisetron compared with ondansetron but the difference was not statistically significant. There were no statistically significant differences in therapeutic success rates, and failure rates between the two drugs. Ondansetron for the Management of CINV in Pediatric Patients 6

One RCT 2 compared ondansetron with granisetron. During both the acute and delayed phases better results were obtained with granisetron with respect to complete response, nausea, vomiting and requirement for additional drug doses, though the results were not always statistically significant. When antiemetic effects were expressed as scores using the Morrow Assessment of Nausea and Emesis (MANE) scale, granisetron was statistically significantly more effective than ondansetron during both the acute and delayed phases. Ondansetron versus palonosetron One systematic review, 13 which included one RCT comparing ondansetron with palonosteron, showed that absence of nausea and complete control of emetic events were greater with palonosetron however it was unclear if the differences were statistically significant. Details are available in Appendix 5. What is the clinical evidence on the safety and harms of ondansetron for the treatment of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients? Adverse events were reported in the two systematic reviews, 1,13 one RCT, 2 and one nonrandomized study. 3 Headache and constipation were the most frequently reported adverse events. Other adverse events included dizziness, loose motion, abdominal pain, hypotension, fatigue, injection site reaction, and allergic reaction. Adverse events appeared to be similar for the various treatments. Details are available in Appendix 5. What are the evidence-based guidelines regarding the use of ondansetron for the treatment of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients? For optimal control of acute CINV in children, one guideline 14 recommended that ondansetron or granisetron be used in combination with dexamethasone for children receiving chemotherapy with drugs of high or moderate emetic risk and ondansetron or granisetron alone for children receiving chemotherapy with drugs of low emetic risk. Another guideline 6 did not specifically mention ondansetron, but recommended a combination of a 5-HT 3 receptor antagonist (which includes ondansetron) plus a corticosteroid before chemotherapy in children undergoing chemotherapy with drugs of high or moderate emetic risk. A list of chemotherapeutic drugs with their associated emetic risks was provided in this guideline. Further details including dose details, strength of recommendation, and evidence ratings are provided in Appendix 6. Limitations Neither of the two included systematic reviews was specifically on ondansetron and included also other antiemetics. Furthermore, one systematic review included a broad population and not just children with chemotherapy induced nausea and vomiting. It included studies on both children and adults and included various conditions (nausea and vomiting resulting from chemotherapy or radiotherapy or post-surgery or during pregnancy). However results of individual studies were presented separately. Neither of the two systematic reviews pooled Ondansetron for the Management of CINV in Pediatric Patients 7

results of the studies as antiemetic doses and antiemetics compared varied. Instead, a qualitative description was provided. The RCTs included in the systematic reviews, included patients with a variety of cancers treated with several different chemotherapeutic agents. Considering the broad population, the effect of ondansetron may be generalizable to some degree. On the other hand, the extent of effect of ondansetron may not always be applicable for a specific type of cancer being treated with specific types of chemotherapeutic agents. In the systematic reviews, comparisons of ondansetron with various drugs or placebo were assessed. However in most instances, for each comparison there was only one relevant study. Hence results need to be interpreted with caution as the quantity of evidence is limited. The definition of outcomes reported in the studies varied or were not provided, so comparisons between study results were difficult. There was limited reporting of adverse events. The included RCT had restrictive inclusion criteria so results may not be applicable to a broader pediatric population. The retrospective study had no comparator group hence one cannot definitively attribute effects specifically to the antiemetic. It contained adverse effects data but no efficacy data. One guideline contained limited information specific for ondansetron. One guideline provided recommendations on the use of ondansetron in pediatric cancer patients undergoing chemotherapy but details of the types of cancer and chemotherapy agents were not provided CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING For the management of CINV in the pediatric population, the antiemetic effects of ondansetron plus dexamethasone appeared to be statistically significantly better than ondansetron alone or placebo. There was no statistically significant difference in antiemetic effect between ondansetron and tropisetron. There were some inconsistencies in the results for antiemetic effects of ondansetron compared with granisetron. Numerical values suggested that the antiemetic effects of palonosetron was greater compared to ondansetron, however it was unclear if the differences were statistically significant. It should be noted that in most instances, for each comparison there was only one relevant study so results need to be interpreted with caution. Headache was the most commonly reported adverse event and appeared to be similar for various drug comparisons; however, adverse events were reported in few of the studies. The guidelines recommended ondansetron as a treatment option for controlling CINV in the pediatric population. One additional guideline 15 had relevant information on ondansetron use but did not report methods for development and hence could not be included. It recommended ondansetron with or without other drugs depending on the circumstances, as first line therapy for CINV in pediatric patients undergoing chemotherapy with drugs of high or moderate emetic risk. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Ondansetron for the Management of CINV in Pediatric Patients 8

REFERENCES 1. Phillips RS, Gopaul S, Gibson F, Houghton E, Craig JV, Light K, et al. Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database Syst Rev. 2010;(9):CD007786. 2. Siddique R, Hafiz MG, Rokeya B, Jamal CY, Islam A. Ondansetron versus granisetron in the prevention of chemotherapy induced nausea and vomiting in children with acute lymphoblastic leukemia. Mymensingh Med J. 2011 Oct;20(4):680-8. 3. Hasler SB, Hirt A, Ridolfi LA, Leibundgut KK, Ammann RA. Safety of ondansetron loading doses in children with cancer. Support Care Cancer [Internet]. 2008 May [cited 2013 Jan 8];16(5):469-75. Available from: http://link.springer.com/content/pdf/10.1007%2fs00520-007-0338-4 4. Cefalo MG, Ruggiero A, Maurizi P, Attina G, Arlotta A, Riccardi R. Pharmacological management of chemotherapy-induced nausea and vomiting in children with cancer. J Chemother. 2009 Dec;21(6):605-10. 5. Jordan K, Roila F, Molassiotis A, Maranzano E, Clark-Snow RA, Feyer P, et al. Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009. Support Care Cancer [Internet]. 2011 Mar [cited 2013 Jan 8];19(Suppl 1):S37-S42. Available from: http://link.springer.com/content/pdf/10.1007%2fs00520-010-0994-7 6. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol [Internet]. 2011 Nov 1 [cited 2013 Jan 8];29(31):4189-98. Available from: http://jco.ascopubs.org/content/29/31/4189.long 7. Hsu ES. A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. Am J Ther. 2010 Sep;17(5):476-86. 8. Lee CY, Ratnapalan S, Thompson M, Nathan PC, Closs J, French A, et al. Unusual reactions to 5-HT3 receptor antagonists in a child with rhabdomyosarcoma. Can J Clin Pharmacol. 2010;17(1):e1-e4. 9. Keller GA, Ponte ML, DiGirolamo G. Other drugs acting on nervous system associated with QT-interval prolongation. Curr Drug Saf. 2010 Jan;5(1):105-11. 10. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 Feb 15 [cited 2013 Jan 23];7:10. Available from: http://www.biomedcentral.com/1471-2288/7/10 11. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2013 Jan 10];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1756728/pdf/v052p00377.pdf Ondansetron for the Management of CINV in Pediatric Patients 9

12. The AGREE Collaboration. Appraisal of guidelines for research and evaluation (AGREE) instrument [Internet]. London: The AGREE Research Trust; 2001 Sep. [cited 2013 Jan 23]. Available from: http://www.agreetrust.org/?o=1085 13. Peterson K, McDonagh M, Carson S. Drug class review: newer antiemetics: final report update 1 [Internet]. Portland (OR): Oregon Health & Science University; 2009. [cited 2013 Jan 8]. Available from: http://www.ncbi.nlm.nih.gov/books/nbk47160/pdf/toc.pdf 14. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients [Internet]. Toronto: Pediatric Oncology Group of Ontario (POGO); 2012. [cited 2013 Jan 8]. Available from: http://www.pogo.ca/_media/file/guidelines/pogo%20acute%20ainv%20guideline%20s eptember%2024%202012.pdf 15. Holden V. Guidelines for the prevention and management of chemotherapy induced nausea and vomiting in children and young people with cancer. [Internet]. Harrogate (UK): Paediatric & Adolescent Haematology & Oncology Group, Yorkshire Cancer Network (NHS); 2012. [cited 2013 Jan 24]. Available from: http://www.yorkshire-cancer- net.org.uk/html/downloads/ycn-hyccn-cyp-guidelines-inducednauseaandvomiting-feb2012- v1.1.pdf Ondansetron for the Management of CINV in Pediatric Patients 10

ABBREVIATIONS AINV BD CI CINV CNS d DB FU G h HT IV m MANE mg M N NR NS O OLD P Pr Plb PO q QDS RCT RR T TDS UK USA antineoplastic induced nausea and vomiting twice a day confidence interval chemotherapy induced nausea and vomiting central nervous system day double blind follow up granisetron hour hydroxytryptamine intraveneous month Morrow Assessment of Nausea and Emesis milligram metoclopramide number of patients not reported not significant ondansetron ondansetron loading dose palonosetron procycldine placebo orally every four times a day randomized controlled trial relative ris tropisetron three times daily United Kingdom United States of America Ondansetron for the Management of CINV in Pediatric Patients 11

APPENDIX 1: Selection of Included Studies 226 citations identified from electronic literature search and screened 213 citations excluded 13 potentially relevant articles retrieved for scrutiny (full text, if available) 5 potentially relevant reports retrieved from other sources (grey literature) 18 potentially relevant reports 12 reports excluded: -irrelevant population (1) -irrelevant outcomes (1) -irrelevant study design (4) -abstract only (1) -already included in at least one of the selected systematic reviews (1) -guideline did not report details of methods (2) -other (review articles, editorials)(2) 6 reports included in review Ondansetron for the Management of CINV in Pediatric Patients 12

APPENDIX 2: Characteristics of Included Studies First Author, Publication Year, Country Study Design, Duration Systematic review and meta-analysis Patient Characteristic s, Sample Size (n) Intervention Comparator s Outcomes Measured Phillips, 1 2010, UK Peterson, 13 2009, USA SR (28 RCTs of which 10 on ondansetron were relevant for this report); Duration: acute and delayed phase SR (34 studies of which 7 on children treated with ondansetron were relevant for this report. Of these 7 there were 6 RTCs and I nonrandomized study); Duration: acute and delayed phase Randomized controlled trials (RCT) Siddique, 2 RCT (DB); 2011, Single center; Bangladesh FU: 4 days Children and young people (age < 18 years) with a diagnosis of cancer and receiving chemotherapy; N= 323 ( in 5 RCTs), in 4 RCTs, episodes not patient number were reported (total episode= 273) and in 1 RCT number of patient or episode was not reported Patients requiring antiemetics for treating or preventing nausea and/or vomiting ( included children treated for chemotherapy induced nausea and vomiting); Patients with acute lymphoblastic leukemia; Age 4 to 11 years; N= 60 (30 in each group) Ondansetron (as well as other antiemetics which are not relevant for this report) Ondansetron (as well as other antiemetics which are not relevant for this report) Ondansetron (4 mg) 30 mins before chemotherapy ; (additional dose only if required) Active comparator or placebo Active comparator or placebo or no comparator Granisetron (1 mg) 30 mins before chemotherapy ; (additional dose only if required) Antiemetic effect; Adverse effects Antiemetic effect; Adverse effects Antiemetic effect (using modified MANE scale); Biochemical markers; Adverse events Ondansetron for the Management of CINV in Pediatric Patients 13

First Author, Publication Year, Country Study Design, Duration Non-randomized studies Hasler, 3 2008, Switzerland Retrospective Single center; Duration: 24 hours after administration of OLD Patient Characteristic s, Sample Size (n) Patients with a diagnosis of cancer (leukemia, Lymphoma, CNS tumor or solid tumor outside CNS) who had received 1 OLD; Age (median [range]) in years: 6.9 [0.4 to 15.7]; N= 37 (37 patients received 543 OLD) Intervention Ondansetron loading dose (OLD) (IV 16mg/m2 [top dose 24 mg] over 15 min, 30 min before starting chemotherapy. Then followed by two IV or oral doses of ondansetron (5mg/m 2 ; top dose, 8 mg) every 8h Comparator s No comparator Outcomes Measured Adverse effects CNS= central nervous system, DB= double blind, FU= follow up, IV= intravenous, MANE= Morrow Assessment of Nausea and Emesis, mg= milligram, N= number of patients, OLD= ondansetron loading doses, UK= United Kingdom, USA= United States of America Ondansetron for the Management of CINV in Pediatric Patients 14

APPENDIX 3: Grading of Recommendations and Levels of Evidence Guideline Society, Country, Author, Year Strength of Recommendation /Level of Evidence POGO, 14 Canada, Lee Dupuis, 2012 Strength of recommendation 1A Strong recommendation, high-quality evidence 1B Strong recommendation, moderate quality evidence 1C Strong recommendation, poor quality evidence Benefit vs risk and burdens Desirable effects clearly outweigh undesirable effects or vice versa p.148 Desirable effects clearly outweigh undesirable effects or vice versa p.148 Desirable effects clearly outweigh undesirable effects or vice versa p.148 Methodology Evidence from well done RCTs or Exceptional observational studies p.148 Evidence from RCTs with some flaws in study or Very strong evidence from observational studies p.148 Evidence of at least one critical outcome from observational studies, case series or RCTs with flaws p.148 Implications Apply to most patients in most circumstances Further research unlikely to change recommendation p.148 Apply to most patients in most circumstances Further research might be helpful p.148 Apply to most patients in many circumstances Further research would be helpful p.148 2A Weak recommendation, high quality evidence 2B Weak recommendation, moderate quality evidence Desirable effects closely balanced with undesirable effects p.148 Desirable effects closely balanced with undesirable effect p.148 Consistent evidence from RCTs without important flaws or Exceptionally strong evidence from observational studies p.148 Evidence from RCTs with important flaws or Very strong evidence from observational studies p.148 Best action may depend on circumstances or patient or society values Further research unlikely to change recommendation p.148 Best action dependent on patient circumstances or patient or society values Further research may change recommendation p.148 Ondansetron for the Management of CINV in Pediatric Patients 15

Guideline Society, Country, Author, Year Strength of Recommendation /Level of Evidence 2C Weak recommendation with poor quality evidence p.148 Desirable effects closely balanced with undesirable effects p.148 Evidence of at least one critical outcome from observational studies, case series or RCTs with serious flaws p.148 Other alternatives may be equally reasonable Further research very likely to change recommendation p.148 Quality of evidence High Further research is very unlikely to change our confidence in the estimate of effect p. 148 Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate p. 148 Low Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate p. 148 Very low Any estimate of effect is very uncertain p. 148 ASCO, 6 USA, Basch, 2011 Levels and grades of evidence for recommendations: Level Grade I: Evidence is obtained from metaanalysis of multiple, welldesigned,controlled studies. Randomized trials have with low false-positive and low false-negative errors (high power). p. 2973* II: Evidence is obtained from at least one well-designed experimental study. Randomized trials have high false-positive and/or -negative errors (low power). p. 2973* III: Evidence is obtained from welldesigned, quasi-experimental studies such as nonrandomized, controlled, single-group, pre-post, cohort, time, or matched case-control series. p. 2973* A: There is evidence of type I or consistent findings from multiple studies of types II, III, and IV. p. 2973* B: There is evidence of types II, III, and IV, and findings are generally consistent. p. 2973* C: There is evidence of types II, III, and IV, but findings are inconsistent. p. 2973* Ondansetron for the Management of CINV in Pediatric Patients 16

Guideline Society, Country, Author, Year Strength of Recommendation /Level of Evidence IV: Evidence is from well-designed, nonexperimental studies, such as comparative and correlational descriptive and case studies. p. 2973* D: There is little or no systematic empirical evidence. p. 2973* V: Evidence is from case reports and clinical examples. p. 2973* *page number refers to page in original ASCO guideline of 1999 Ondansetron for the Management of CINV in Pediatric Patients 17

APPENDIX 4: Summary of Study Strengths and Limitations First Author, Strengths Publication Year, Country Systematic review and meta-analysis Phillips, 1 2010, UK The objective was stated. The inclusion and exclusion criteria were stated. Comprehensive literature search (multiple database searched) Study selection described and flow chart presented List of included and excluded studies provided Article selection and data extraction were done in duplicate Characteristics of the individual studies were provided Quality assessments of studies were conducted Declaration of interest was stated and there was no financial conflict of interest. Limitations Publication bias was not explored (The drugs compared in the included studies varied and for each comparison in most instances there was one study) Peterson, 13 2009, USA The objective was stated. The inclusion and exclusion criteria were stated. Comprehensive literature search (multiple database searched) Study selection described and flow chart presented List of included and excluded studies provided Article selection was done in duplicate Characteristics of the individual studies were provided Quality assessments of studies were conducted Declaration of interest was stated Unclear if data extraction was done in duplicate Publication bias was not explored Randomized controlled trials (RCT) Siddique, 2 2011, Objectives were stated. Bangladesh Inclusion criteria were stated, exclusion criteria implied. Patient characteristics, interventions, and outcomes were described but details of patient characteristics were not provided. Randomized (double blind: patient Sample size calculations not described Patient characteristics for the two groups not provided separately. Unclear if all patients completed the study Generalizability limited; uncertain as to whether study patients were Ondansetron for the Management of CINV in Pediatric Patients 18

First Author, Publication Year, Country Strengths and investigator blinded) based on random sampling (Drugs were supplied with code numbers) P-values provided Limitations representative of all patients. Non-randomized studies Hasler, 3 2008, Switzerland Objectives were stated. Inclusion criteria were stated Patient characteristics, interventions, and outcomes were described Generalizable to some extent as patients with a variety of cancers were included. Data extracted retrospectively from patient records No comparator Guidelines POGO, Lee Dupuis, 14 2012, Canada, ASCO, Basch, 6 2011, USA The scope and purpose were stated. The guideline development group comprised of individuals from relevant areas. The methods used for the development of the guidelines were rigorous. Recommendations were clear Organizational barriers and cost implications were mentioned Declaration of interest of guideline development members were stated The scope and purpose were stated. The guideline development group comprised of individuals from relevant areas. The methods used for the development of the guidelines were rigorous. Recommendations were clear Declaration of interest of guideline development members were stated Unclear if patient input was sought. Organizational barriers and cost implications were not mentioned Unclear if patient input was sought. Ondansetron for the Management of CINV in Pediatric Patients 19

APPENDIX 5: Main Study Findings and Authors Conclusions First Author, Main Findings and Authors Conclusion Publication Year, Country Systematic review and meta-analysis Phillips, 1 2010, UK 159 patients 31 patients 49 episodes O vs O Intervention Ondansetron 5 mg/ m² IV over 15 minutes immediately prior to chemotherapy, then at +8 hours and +16. Ongoing ondansetron given orally < 1 m² 4 mg TDS, > 1 m² 8 mg TDS, continued for 3 days after last day of chemotherapy or 5 days if nausea and vomiting persisted p. 58 O vs O Ondansetron 0.6 mg/kg (max 32 mg) IV over 30 minutes before Chemotherapy p. 59 O vs T Ondansetron 0.45 mg/kg IV 15 minutes after Chemotherapy p. 59 Comparator Ondansetron 10 mg/m² IV over 15 minutes immediately prior to chemotherapy, then 5 mg/m² IV at +8 hours and +16. Ongoing ondansetron given orally < 1 m² 4 mg TDS, > 1 m² 8 mg TDS, continued for 3 days after last day of chemotherapy or 5 days if nausea and vomiting persisted p. 58 Ondansetron 0.15 mg/kg (max 8 mg) IV over 30 minutes before chemotherapy then every 4 hours for a total of 4 doses p.59 Tropisetron 0.20 mg/kg IV 15 minutes after Chemotherapy p. 59 1.01 (0.81, 1.25) 1.25 (0.70, 2.22) 0.97 (0.54, 1.69) Main Findings: Complete control of acute nausea (results from individual RCTs) Number assessed Comparison Dosage RR (95% CI) Complete control of delayed nausea (results from individual RCTs) Number assessed Comparison Dosage RR (95% CI) 49 episodes O vs T Intervention Ondansetron 0.45 mg/kg IV 15 minutes after Chemotherapy p. 59 Comparator Tropisetron 0.20 mg/kg IV 15 minutes after Chemotherapy p. 59 1.03 (0.54, 1.69) Ondansetron for the Management of CINV in Pediatric Patients 20

First Author, Publication Year, Country Main Findings and Authors Conclusion Complete control of acute vomiting (results from individual RCTs) Number assessed Comparison Dosage RR (95% CI) 159 patients 52 patients 31 patients 60 episodes 49 episodes 30 patients O vs O Intervention Ondansetron 5 mg/ m² IV over 15 minutes immediately prior to chemotherapy, then at +8 hours and +16. Ongoing ondansetron given orally < 1 m² 4 mg TDS, > 1 m² 8 mg TDS, continued for 3 days after last day of chemotherapy or 5 days if nausea and vomiting persisted p. 58 O vs O Ondansetron 8 mg PO BD plus 4 to 8mg dexamethasone IV p. 63 O vs O Ondansetron 0.6 mg/kg (max 32 mg) IV over 30 minutes before Chemotherapy p. 59 (O+D) vs O O vs T O vs (M+Pr+D) Ondansetron, IV, 0.15 mg/kg 30 minutes prior to chemotherapy, then BD on chemotherapy for 1 to 5 days plus dexamethasone either 4 mg/m²qds or 8 mg/m² BD (depended on institution) p.60 Ondansetron 0.45 mg/kg IV 15 minutes after Chemotherapy p. 59 Ondansetron 3 to 8mg/m² given pre-chemotherapy, then BD initially IV then orally for 3 days p. Comparator Ondansetron 10 mg/m² IV over 15 minutes immediately prior to chemotherapy, then 5 mg/m² IV at +8 hours and +16. Ongoing ondansetron given orally < 1 m² 4 mg TDS, > 1 m² 8 mg TDS, continued for 3 days after last day of chemotherapy or 5 days if nausea and vomiting persisted p. 58 «Ondansetron 5 mg/ m² IV BD plus 4 to 8 mg dexamethasone IV p. 63 Ondansetron 0.15 mg/kg (max 8 mg) IV over 30 minutes before chemotherapy then every 4 hours for a total of 4 doses p.59 Ondansetron, IV, 0.15 mg/kg 30 minutes prior to chemotherapy, then BD on chemo for 1 to 5 days p.60 Tropisetron 0.20 mg/kg IV 15 minutes after Chemotherapy p. 59 Metoclopramide 10 mg/ m² IV QDS for 3 days, with 2.5 mg procyclidine. Dexamethasone 0.89 (0.72, 1.00) 1.04 (0.62, 1.75) 0.94 (0.49, 1.79) 2.43 (1.76, 3.34) 1.11 (0.64, 1.93) 3.67 (2.25, 5.98) Ondansetron for the Management of CINV in Pediatric Patients 21

First Author, Publication Year, Country Main Findings and Authors Conclusion 66 episodes 98 episodes G vs O Plb vs O 61 4mg/m² IV then 2 mg/m² TDS IV or PO p.61 Oral granisetron single dose 1 hour before administration of chemotherapy p.62 Placebo (saline) IV 15- minute infusion 30 minutes prior to lumbar puncture p. 63 Ondansetron 0.15 mg/kg IV 1 hour before chemotherapy and 4 hours after the first dose. Oral dose given 8 hours after the first dose p. 62 Ondansetron 5 mg/ m² IV BD plus 4 to 8 mg dexamethasone IV p.63 0.75 (0.52, 1.09) 0.51 (0.38, 0.69) 49 episodes O vs T Intervention Ondansetron 0.45 mg/kg IV 15 minutes after Chemotherapy p. 59 Comparator Tropisetron 0.20 mg/kg IV 15 minutes after Chemotherapy p. 59 0.93 (0.53, 1.63) Complete control of delayed vomiting (results from individual RCTs) Number assessed Comparison Dosage RR (95% CI) Complete control of acute nausea and vomiting (results from individual RCTs) Number assessed Comparison Dosage RR (95% CI) Intervention Comparator 30 patients 31 patients O vs (M+Pr+D) Ondansetron 3 to 8mg/m² given pre-chemotherapy, then BD initially IV then orally for 3 days p. 61 O vs O Ondansetron 0.6 mg/kg (max 32 mg) IV over 30 minutes before Chemotherapy p. 59 Metoclopramide 10 mg/ m² IV QDS for 3 days, with 2.5 mg procyclidine. Dexamethasone 4mg/m² IV then 2 mg/m² TDS IV or PO p.61 Ondansetron 0.15 mg/kg (max 8 mg) IV over 30 minutes before chemotherapy then every 4 hours for a total of 4 doses p.59 3.67 (2.25, 5.98) 1.25 (0.70, 2.23) Adverse effects (results from individual RCTs) Number Adverse effect assessed 159 patients Ondansetron (5 mg/m2): headache and dizziness in 2 patients, and headache and warm feeling in 2 patients. Ondansetron (10 mg/m2): headache in one patient 30 patients Ondansetron: leg pains in 1 patient. Ondansetron for the Management of CINV in Pediatric Patients 22

First Author, Publication Year, Country Main Findings and Authors Conclusion Metoclopramide and dexamethasone: stomach aches in 2 patients, agitation/behavior in 2 patients and tiredness in 1 patient. NR Ondansetron: headache in 8 patients. Perphenazine and diphenylhtdramine: dystonia in 2 patients and mild-moderate sedation in 24 patients Authors Conclusion: Our overall knowledge of the most effective antiemetics to prevent chemotherapyinduced nausea and vomiting in childhood is in complete. Future research should be undertaken in consultation with children, young people and families that have experienced chemotherapy and should make use of validated, age-appropriate measures. This review suggests that 5-HT 3 antagonists with dexamethasone added are effective in patients who are to receive highly emetogenic chemotherapy although the risk-benefit profile of additional steroid remains unclear. p. 2 Peterson, 13 2009, USA Main Findings: Results from individual RCTs Number of Comparison Results patients 33 G vs O G: (PO, 0.5 or 1.0 mg); O: (IV, 0.45 mg/kg) Complete response(no emetic episode and no need for rescue medication) within 24h: 60.6% vs 45.5%, NS Incomplete response: 39.4% vs 54.5%, NS Therapeutic success: 84.8% vs 87.9%, NS Failure ( 3 vomiting episodes in 24h): 15% vs 12%, NS Adverse events were similar in both groups. Headache and constipation were the most frequently reported adverse events. 90 O vs G vs T O: (IV, 5.3 mg/m 2 ); G: (IV, 2mg/m 2 ); T: (IV, 3.3mg/m 2 ) Complete response (no vomiting or retching): 58.3% vs 62.9% vs 57.1%, NS Partial response (1 4 vomiting episodes/day) in % of patient days: 34.2% vs 28.2% vs 38.3%, NS Failure ( 5 vomiting episodes/day) in % of patient days: Ondansetron for the Management of CINV in Pediatric Patients 23

First Author, Publication Year, Country Main Findings and Authors Conclusion 7.5% vs 8.9% vs 4.6%, NS Headache was the only reported adverse event and it was mild. The frequency was similar in all three groups. 100 P vs O P: (IV 0.25 mg) O: (IV, 8mg/m 2 ); Response Day Complete control of emetic events Absence of nausea 1 92% vs 72% 74% vs 38% 2 72% vs 46% 62% vs 18% 3 78% vs 54% 72% vs 30% 4 88% vs 84% 88% vs 58% 5 98% vs 90% 98% vs 88% 6 100% vs 94% 98% vs 92% 7 100% vs 96% 98% vs 94% 428 O IV vs O PO O(IV 5mg/m 2 ) vs O (PO, 8 mg) Complete control of emesis (0 episodes): Treatment day 1: 81% vs 78%, NS Treatment phase A: 73% vs 71%, NS Overall treatment phase (A&B): 62% vs 62%, NS Major control of emesis (1-2 episodes): Treatment day 1: 10% vs 13%, NS Treatment phase A: 16% vs 17%, NS Overall treatment phase (A&B): 23% vs 29%, NS Mild nausea: Treatment day 1: 21% vs 21%, NS Treatment phase A: 26% vs 26%, NS Overall treatment phase (A&B): 36% vs 33%, NS No nausea: Treatment day 1:73% vs 70%, NS Treatment phase A: 64% vs 64%, NS Overall treatment phase (A&B): 52% vs 56%, NS Authors Conclusion: For dolasetron, granisetron and ondansetron: No consistent significant differences on any antiemetic efficacy outcomes, regardless of population or formulation p. 44 For palonosetron compared to ondansetron in children receiving chemotherapy; Possibly superior for early complete response rates following highly emetic chemotherapy p. 45 Ondansetron for the Management of CINV in Pediatric Patients 24

First Author, Main Findings and Authors Conclusion Publication Year, Country Randomized controlled trials (RCT) Siddique, 2 2011, Main Findings: Effect (expressed as number [%] of patients) Bangladesh Outcome Time period (day) Effect Ondansetron (N=30) Complete response P- value Granisetron (N= 30) 1 21 (70.0%) 27 (90.0%) 0.053 2 18 (60.0%) 28 (93.3%) 0.230 3 17 (58.6%) 26 (86.7%) 0.015 4 17 (58.6%) 29 (96.7%) 0.002 Nausea 1 5 (16.7%) 2 (6.7%) 0.424 2 8 (26.7%) 1 (3.3%) 0.026 3 10 (33.3%) 2 (6.7%) 0.010 4 11 (36.7%) 1 (3.3%) 0.001 Vomiting 1 8 (26.7%) 1 (3.3%) 0.026 2 10 (33.3%) 1 (3.3%) 0.003 3 6 (20.0%) 2 (6.7%) 0.254 4 1 (3.3%) 0 0.999 Additional dose required 1 5 (16.7%) 0 0.050 2 9 (30%) 1 (3.3%) 0.0120 3 5 (16.7%) 2 (6.7%) 0.424 4 1 (3.3%) 0 0.001 Effect (expressed as scores for nausea and vomiting using MANE scale) Outcome Time period Effect P-value (day) Ondansetron (N=30) Granisetron (N= 30) Score with 1 1.73± 3.00 0.23± 0.73 0.012 MANE scale 2 3.07± 5.13 0.27± 1.14 0.006 3 2.31± 3.64 0.57± 1.61 0.023 4 1.07± 2.17 0.07± 0.37 0.020 Adverse effects Outcome Effect P-value Ondansetron (N=30) Granisetron (N= 30) Headache 16.7% 10% >0.05 Constipation 16.7% 13.3% >0.05 Abdominal pain NR* NR* NS Loose motion NR* NR* NS Decreased appetite NR* NR* NS *results were presented in a figure but specific values were not reported Authors Conclusion: Both oral ondansetron andgranisetron are well tolerated and effective but granisetron is more effective in controlling acute and delayed onset chemotherapy (HDMTX) Ondansetron for the Management of CINV in Pediatric Patients 25